The Peter Attia Drive - #352 ‒ Female fertility： optimizing reproductive health, diagnosing and treating infertility and PCOS, and understanding the IVF process ｜ Paula Amato, M.D.

00:00:00.000 Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Atiyah. This podcast,

00:00:16.540 my website, and my weekly newsletter all focus on the goal of translating the science of longevity

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00:00:53.200 of the subscription. If you want to learn more about the benefits of our premium membership,

00:00:58.020 head over to peteratiyahmd.com forward slash subscribe. My guest this week is Dr. Paula Amato.

00:01:06.980 Paula is a professor of OBGYN at Oregon Health and Science University and a leading expert

00:01:13.120 in reproductive endocrinology and infertility. She's been on the forefront of research and

00:01:19.380 clinical practice of IVF, fertility, preservation, and reproductive aging. And today we then continue

00:01:25.660 our two-part series on infertility. Last week, of course, we covered the male side of this with

00:01:31.300 Dr. Paul Turek, and this week we're talking more about female infertility with Paula. In this episode,

00:01:37.360 we discuss the biology of female fertility, how hormonal shifts drive the menstrual cycle and regulate

00:01:43.220 ovulation, and what those patterns reveal about fertility potential. How infertility is defined,

00:01:49.000 where to begin a workup, and why both partners should be evaluated early. The role of the fallopian tube

00:01:55.140 in natural conception and how infections and or structural issues can lead to infertility

00:02:00.720 or ectopic pregnancy. The reality of miscarriage and why most early losses are due to chromosomal

00:02:06.840 abnormalities, not anything the patient is doing wrong. Increasing impact of age, lifestyle,

00:02:12.580 and environmental factors on fertility, especially as more people delay childbearing. Causes and treatment

00:02:18.480 options for polycystic ovarian syndrome, PCOS. The emergence of GLP-1 agonists in PCOS and what we

00:02:26.440 know and don't know yet about their impact on fertility and pregnancy safety. The nuances of

00:02:32.160 diagnosing and treating unexplained infertility and how age and ovarian reserve shape clinical decisions.

00:02:38.620 The evolution of IVF from early methods of today's technologies, including the use of pre-implantation

00:02:45.020 genetic testing, considerations around egg freezing, how timing, age, and egg quantity influence outcomes

00:02:52.340 and decision-making, promise and limitations of next-gen reproductive technologies, such as

00:02:57.940 mitochondrial replacement, and many other things. So without further delay, please enjoy my conversation

00:03:04.640 with Dr. Paula Amato. Hey, Paula, thank you so much for coming to Austin and sitting down to share some

00:03:16.720 remarkable insights. Listeners last week will have heard us talk about all things that pertain to

00:03:21.380 male fertility. And as promised, we're going to now talk about fertility, but from the female

00:03:26.680 perspective, the physiology here is different, but no less complex. And there was some pretty unique

00:03:31.800 things about it. One of them being that unlike sperm, which seemed to be an infinite resource,

00:03:37.760 men are constantly generating literally billions of these things. The exact opposite is the case

00:03:42.500 with women. Tell us a bit about that. That's right. First, thanks for having me. Thanks for inviting me.

00:03:46.760 It is true that when an embryo or fetus develops, the gonad differentiates into either a testes or an

00:03:55.360 ovary. And the main difference, as you said, is that sperm is produced throughout a man's lifetime,

00:04:00.960 whereas women are born with a finite number of eggs. Actually, the most eggs you'll ever have is 0.89

00:04:06.720 when you're in your mom's womb as a fetus. And by the time you're born, there's about 2 million or

00:04:12.300 so eggs. And by the time you start menstruating, you're down to maybe 400,000 or so.

00:04:18.440 Wow. So a five-fold reduction from birth to, say, average age would be maybe 14?

00:04:24.320 Yeah, 12 to 14. And we don't know why exactly that happens, but most of the eggs in the ovaries

00:04:30.200 actually undergo a process we call atresia. They basically die. So once a woman goes through 1.00

00:04:35.940 puberty or a girl goes through puberty every month, if she's not on hormonal contraception,

00:04:41.700 one of those eggs grows. Actually, probably a group of eggs every month starts to grow,

00:04:47.140 but then one takes over and is released from the ovary and usually finds its way into the 0.90

00:04:54.140 fallopian tubes. That's the tube connecting the ovary and the uterus. And then normally,

00:04:59.840 if there's not sperm around, the egg just resorbs and there's no pregnancy and the lining of the

00:05:05.860 uterus sheds and a girl or woman has a period every month. If there's sperm around, there's a chance that 0.82

00:05:12.080 that egg might fertilize and that fertilization usually happens in the fallopian tube actually.

00:05:17.660 And then that now zygote or embryo travels down the tube into the uterus and some of the time

00:05:25.140 implants into the wall of the uterus or the lining of the uterus and establishes a pregnancy.

00:05:32.200 Okay. So let's now talk about a woman in the prime of her reproductive age. She's 20 years old, 1.00

00:05:37.900 as an example. And let's talk through the cycle of what is happening and the role that hormones are

00:05:45.780 playing. One of the things that to me has always been fascinating about this is the selection.

00:05:50.760 So with males, we don't have to think about that problem. The selection tends to be maybe more

00:05:55.540 metabolic or stochastic. In other words, which sperm is the sperm that makes it isn't really

00:06:01.820 predetermined. How is it that let's say from day zero, when a woman begins her menstrual cycle 0.52

00:06:09.040 and all of a sudden everything starts to turn towards the next cycle, she's about 14 days out

00:06:14.880 from ovulation. We start to see the interplay of luteinizing hormone and follicle stimulating

00:06:20.200 hormone, particularly FSH. Walk me through what's happening in that period of time that ultimately leads

00:06:26.000 to one and only one egg being the chosen one. Yeah. It's a little random in women as well, 1.00

00:06:32.340 actually. But it's true that the pituitary hormones, namely FSH or follicle stimulating hormone

00:06:39.080 and LH luteinizing hormone are what drives growth of the, we call them follicles. The eggs are inside

00:06:46.540 the follicles. And as I said, usually a cohort of eggs starts to grow. Tell me what grow means.

00:06:52.600 The follicles start to get bigger and the cells surrounding the eggs start to divide.

00:07:00.520 And what do they look like prior to all of that happening? These are cells

00:07:03.780 that only have 50% of the genetic material. They've already undergone meiosis.

00:07:10.880 Yes. Meiosis, they're kind of arrested in meiosis and meiosis not completed until they actually 0.93

00:07:17.880 ovulate and then in some cases are fertilized. So we have an arrested cell that has one of each

00:07:26.980 of the mother's chromosomes, including one X chromosome by definition, one of her two sex

00:07:32.920 hormones. And I don't know if this question makes sense, but is it still in its young phenotype? In other

00:07:40.380 words, if the woman is 20 years old and all of the cells in her body are functionally 20 years old,

00:07:46.260 is this egg prior to ovulation still basically an infant cell?

00:07:52.900 As far as we know, although there's some data recently to suggest that perhaps the cells surrounding

00:08:00.620 the egg are metabolically active and may be aging. Certainly we do know that the quality of the eggs

00:08:09.820 decreases, right, as women get older. So that affects how the eggs and the chromosomes ultimately 0.98

00:08:17.200 divide. That's part of the reason it's harder to get pregnant as you get older. Even though you're 0.97

00:08:22.340 ovulating, you may be releasing an egg every month, but that egg could be abnormal. And if it's abnormal,

00:08:28.240 it likely won't fertilize. And you kind of don't want it to fertilize if it's abnormal and establish

00:08:32.620 your pregnancy. But you're right, they're pretty much arrested in time, certainly before puberty.

00:08:39.580 And then every month, a few start to develop. And then one, we don't really know how that one egg

00:08:46.380 is selected. Definitely hormonal factors play a role, but it's somewhat random. One kind of grows

00:08:52.940 and then eventually is released.

00:08:55.420 Now, not to anthropomorphize this too much, but one would sort of assume that natural selection

00:09:03.080 runs strong. And if a woman, by the time she begins her fertility stage of life, has 400,000 eggs,

00:09:13.420 just say on average, she only has a finite number of shots on goal. Let's just say 12 per year. And I 0.86

00:09:21.860 don't know, let's just say, if you look at peak reproductive, maybe 20 years, that's a tiny sliver

00:09:27.780 of 400,000. That's true.

00:09:29.920 You would have to assume that there is some selection that's happening to pick the best

00:09:35.640 few hundred of those 400,000. Is there any evidence that that's happening?

00:09:40.420 Only in that the ones that usually result in pregnancy are chromosomally normal. So most of the

00:09:48.160 embryos are chromosomally abnormal, and that's because most of the eggs are chromosomally

00:09:53.540 abnormal. So there is selection in that sense. Most of the time, only the chromosomally normal

00:09:59.500 embryos are the ones that implant and continue to develop.

00:10:03.960 And when you say chromosomally normal, are you referring to the egg or the zygote?

00:10:08.080 The zygote, but most of the abnormalities in chromosomes that happen in a zygote are believed

00:10:14.160 to be related to maternal age. And does that mean we think that the abnormality occurred

00:10:20.800 way before ovulation? Or when do we think that that occurred?

00:10:25.680 We think it occurred in the stage of meiosis that happens as the egg is developing that month.

00:10:32.600 That ripening phase.

00:10:34.140 So explain how that happens. If you were to sample eggs from a five-year-old girl,

00:10:39.860 nowhere near reproductive age. So every one of those is in a state of frozen meiosis.

00:10:46.280 How many things have to happen before it is ready to undergo full meiosis? In other words,

00:10:52.160 how does it go from that stage to, I'm sorry for using big words to the listener, and please feel

00:10:57.720 free to explain what I mean by aneuploidy, but how do you go from that frozen meiotic state to an 0.98

00:11:03.340 aneuploidic state? And please explain what I just said to people.

00:11:05.880 Sure, sure. It's a little bit of a black box, of course, because we can't see exactly what's

00:11:10.440 happening. But the way we understand it is that the cells start off, including egg cells,

00:11:17.120 as having two copies of each chromosome, but eventually has to become one copy in order to

00:11:24.380 combine with a sperm that also has one copy of each chromosome. So during that process,

00:11:31.700 there has to be disjunction of each of the pairs of chromosomes. So there are 23 pairs of chromosomes,

00:11:38.940 including X and Y, the sex chromosomes. And during that disjunction phase is when we think most of the

00:11:45.460 errors happen. Because if they don't divide evenly, like 23 and 23, you're going to get an extra one,

00:11:52.300 you're going to be missing one. And then when it combines with sperm that also has a haploid set of

00:11:57.280 chromosomes, there's going to be an abnormal number, and that affects development.

00:12:01.040 And that completion only occurs during the 14 days leading to ovulation?

00:12:07.040 Ovulation and then fertilization, yes.

00:12:09.860 Okay. So that explains why, to my earlier question, there must be something, even though they are

00:12:16.900 quote unquote frozen in time, there is either something going on with the egg or maybe the

00:12:23.180 metabolic milieu around the egg from those cells that is changing the probability of success

00:12:30.100 for that division of genetic material.

00:12:35.020 Right.

00:12:35.880 As we know that as a woman ages, the probability of successful division goes down. 1.00

00:12:40.520 Right. So something changes as a woman ages, but we don't understand exactly. But whatever it is

00:12:46.820 that's going on makes those chromosome errors much more likely.

00:12:51.000 Yeah. I'll tell you a very interesting story. A very close friend of mine has a son with Down

00:12:56.100 Syndrome and he's probably 20 now. So this is, the story I'm telling occurred roughly 20 years ago.

00:13:01.680 So when their son was born, I believe he was their third child. This is probably at a time,

00:13:06.700 I don't think they knew until this was, in fact, I know that they didn't know until birth.

00:13:10.140 They hadn't done amniocentesis or anything like that. They're sort of dealing with this,

00:13:14.020 right? In the aftermath of their son's birth. And the doctor, the GYN came in and my friend says,

00:13:20.340 you never forget this. The guy looked straight at his wife and said, look, it's important for you

00:13:26.560 to understand that this is your fault. And my friend said he wanted to jump across the table

00:13:33.080 and kill this guy. 0.76

00:13:34.480 Yeah. I don't blame him.

00:13:35.820 But then what he realized is what he was actually saying is this is the result of the egg releasing

00:13:43.440 one too many. He had two copies of, was it 21?

00:13:47.500 Yeah. So two copies of 21 instead of one copy of 21 came from the egg. It's interesting. My friend

00:13:52.960 and I have talked about this many times since. And he said, I really came to appreciate what he was

00:13:57.220 trying to do there, albeit in an completely clumsy way. He was just trying to explain that there is a

00:14:04.420 reason for this. It is maternal and whatever. But anyway, it always stuck with me is that's a great

00:14:09.440 lesson in bad bedside manner. For sure.

00:14:11.500 Yeah. But he made the point. The point here being is while trisomy 21 is a very common form of

00:14:20.120 aneuploidy, it's also not lethal. There are many lethal forms of aneuploidy as well.

00:14:24.980 Right. Right. Trisomy 21 can be lethal, but not always. So some of those pregnancies do continue.

00:14:31.380 Depending on the chromosomal abnormalities, some only develop to a certain point and then stop

00:14:36.140 developing. And some are actually compatible with live birth, but usually have some abnormalities.

00:14:42.840 And do we know, for example, that if you were to look at all miscarriages that occur

00:14:47.480 inside the first trimester, would you be able to hazard a guess as to what percentage of all

00:14:52.660 miscarriages inside of 13 weeks are likely the result of aneuploidy?

00:14:57.720 Definitely the majority of them, probably close to 90% of them.

00:15:00.900 Yeah. Okay. So in other words, maybe someone listening to this who's experienced miscarriages

00:15:07.580 early in a pregnancy can take some solace in understanding that that was the body's way

00:15:13.880 of correcting something that was inevitable sooner rather than later.

00:15:17.340 Yeah. I think that's true. Yeah. Miscarriages are very common and that's the most common cause.

00:15:22.920 Although there are other causes, usually we don't do a whole lot of testing if it's just one

00:15:28.680 miscarriage because that's very common. We just assume fetus or embryo was abnormal. But if a woman 1.00

00:15:34.280 has two in a row, then that warrants some additional testing.

00:15:37.500 Regardless of her age?

00:15:39.160 Regardless of her age. Obviously, the chances of finding something else goes down as a woman gets 1.00

00:15:45.220 older because you don't want to miss another cause that's potentially treatable.

00:15:49.780 Okay. Well, let's put a pin in that because I actually want to understand that more.

00:15:52.520 But that's interesting to me that if a 40-year-old woman had successive 1.00

00:15:56.640 miscarriages, you wouldn't just chalk it up to, well, she's 40. Of course, 0.56

00:16:01.200 these are aneuploidic eggs.

00:16:02.800 Yeah, that's true. I mean, that's most likely.

00:16:04.860 Most likely.

00:16:05.200 But again, you don't want to miss, especially at 40, you don't want to miss some treatable,

00:16:09.420 other treatable costs.

00:16:09.960 Right. Because you only have so much time.

00:16:12.500 One of the lessons here, hopefully for people listening, is if a couple miscarriages,

00:16:17.660 they shouldn't feel that they've done something wrong.

00:16:19.580 The woman shouldn't beat herself up thinking, oh my God, did I have one too many cups of coffee or 1.00

00:16:24.540 was I under too much stress? No. Greater than 90% chance this was a bad split.

00:16:30.540 Yes.

00:16:30.740 And that's the way it works.

00:16:31.560 Yes.

00:16:31.740 Okay. So let's go back to this process. So it's day zero. So a woman just begins her period. We're 0.95

00:16:38.680 just getting ready to embark on her next fertility cycle. The pituitary gland is secreting luteinizing 1.00

00:16:45.300 hormone and follicle stimulating hormone. Walk me through what is happening in the next 14 days that

00:16:50.920 leads to that ovulation. 0.79

00:16:52.380 So a group of eggs or follicles are starting to grow. One gets selected. We don't really

00:16:57.440 understand.

00:16:57.840 We still don't know how.

00:16:58.300 We don't understand why. It's random. And that follicle that's in a follicle,

00:17:03.560 follicle is kind of a fluid filled cyst like structure that surrounds each egg. So that continues

00:17:09.520 to grow. And then eventually what's happening hormonally. So those cells surrounding the eggs

00:17:16.440 are producing estrogen. That estrogen is preparing, acting on the uterine lining to build up the

00:17:22.500 lining to potentially support a pregnancy. And then what happens just before ovulation

00:17:27.680 is there's a surge in a hormone called LH, luteinizing hormone. And that's what we think

00:17:33.820 triggers ovulation or release of an egg. So all that has to happen before an egg is released.

00:17:40.960 So it busts out of the ovary, finds its way to the tube. 0.82

00:17:46.340 How energetically demanding is that? We learned last week in talking with Paul that the ATP

00:17:53.160 requirement for those sperm to travel all that distance is unbelievable. How passive versus

00:18:01.400 active is the movement of that egg? How metabolically demanding is it?

00:18:05.140 I don't know that we understand it completely, but you would imagine that their energy is

00:18:10.440 required for that to happen certainly. So it's not passive. It's not just sort of a

00:18:14.960 diffusion down the fallopian tube. Right. Prostaglandins are involved and

00:18:20.180 calcium, all kinds of things have to happen for that process to occur.

00:18:24.660 Okay. How long approximately, just give people a sense of how long a fallopian tube is?

00:18:29.820 Probably a few centimeters, five to 10.

00:18:32.420 Okay. Everyone's probably used to seeing the image of ovaries being these little eggs and 1.00

00:18:36.860 fallopian tubes having these little fingers that hug up on the eggs.

00:18:39.760 What is actually in between that space? How does the egg get from an ovary into a fallopian tube?

00:18:45.380 Is there an actual connection there?

00:18:46.700 There is actually. They're not stuck together, but they're kind of in close proximity so that

00:18:52.180 those fimbriae or finger-like projections kind of sweep up the egg once it's released from the ovary.

00:18:58.960 Got it. And it's otherwise in direct contact with the peritoneum?

00:19:02.820 The ovary and the tubes? 0.64

00:19:04.260 The space between them.

00:19:05.640 Yeah. The pictures always show like the tubes out here and the eggs out here,

00:19:10.300 but they're actually, everything's closer together in the pelvis.

00:19:13.500 Okay. So egg is now in fallopian tube. How long does it take to get through the length of the

00:19:20.160 fallopian tube into the uterus?

00:19:22.140 About five or six days.

00:19:23.420 Okay. So completely different experience from the sperm, which are racing at breakneck speed

00:19:29.280 and cover that distance in seconds. So what regulates the speed with which

00:19:35.280 the egg travels through the fallopian tube and how does that impact fertility?

00:19:39.160 Is there a scenario whereby it happens too quickly and things don't work?

00:19:42.460 I don't know about too quickly, but there are hair-like projections in the tube cilia that

00:19:47.020 help with motility of the egg down the fallopian tube into the uterus. The abnormalities on the

00:19:55.700 female side, dental abnormalities have to do with like scarring in the tubes or if the tubes are blocked 0.95

00:20:01.480 and then it interferes with the egg encountering the sperm.

00:20:06.600 What leads to that?

00:20:07.260 A number of different things. Infection probably most commonly, but also scarring from previous

00:20:13.280 surgery potentially or a condition called endometriosis. So there are a number of things

00:20:18.180 that can affect the tubes as well.

00:20:21.000 Is the day four, assuming a woman's cycle is predictable and normal and would just say day 14 1.00

00:20:25.460 is ovulation, that is the day that the egg leaves the ovary or that is the day that the egg

00:20:32.640 reaches a certain place within the fallopian tube?

00:20:34.440 Pretty much the day that the egg is released from the ovary. Yeah. And you usually encounter

00:20:40.600 sperm in the fallopian tube and that's where fertilization usually happens. And then it takes 0.99

00:20:46.200 a few more days for the embryo now or pre-embryo to travel down the rest of the tube into the uterus 0.99

00:20:53.760 and hopefully implant if it's normal.

00:20:56.460 Now, one of the most interesting things here that is worth repeating, even though we talked

00:21:00.220 about it last week in case anybody missed it, how many sperm is the egg encountering at the

00:21:05.980 time of fertilization?

00:21:07.780 Millions.

00:21:08.220 Yeah, millions. So why is it, I know the answer to this question, but it is so cool. Why is

00:21:13.380 it that one and only one sperm out of millions or even less than that, but let's just say it's

00:21:20.020 hundreds of thousands. Why does only one get to transmit its genetic material into that egg?

00:21:26.000 Well, once an egg is fertilized, there's sort of a chemical reaction, if you will, that happens

00:21:31.340 that prevents any other sperm from fertilizing the eggs because that would be bad. You only want one 0.89

00:21:36.560 sperm and one egg to combine.

00:21:38.340 Yeah. There's like an electrical force field that immediately activates around the egg. I find this

00:21:44.040 so fascinating and brilliant. Okay. So now, and by the way, what is the relative size of an egg to

00:21:50.480 a sperm?

00:21:51.340 The egg is actually much bigger than the sperm. I don't know exactly in microns how big it is.

00:21:56.620 I feel like I used to know this answer and it's shocking how disparate they are in size.

00:22:01.060 The egg is, I believe, the biggest cell on the body potentially. I've checked on that,

00:22:05.440 but I believe that's true.

00:22:06.740 All right. So yeah, you have this massive egg that's basically like the sun and like this tiny

00:22:11.980 little sperm, which is like the earth and colliding with it. Okay. So fertilization takes place and how

00:22:18.460 long from impact until you have that single cell zygote that actually has a lined up pair of

00:22:26.920 chromosomes? Is that a matter of hours?

00:22:29.320 Yeah. Within a few hours.

00:22:30.420 Okay. And then what is the process that occurs for cell division for when that zygote goes from one

00:22:37.480 to two to four to eight cells? So A, how long does that take? And B, at what point does it implant

00:22:44.200 into the uterus? 0.51

00:22:45.900 Most of what we know actually about this is from in vitro fertilization or IVF, because we can actually

00:22:51.820 see that happening in the Petri dish. So usually with IVF, an egg is fertilized with sperm. By the next

00:22:59.460 day, we can see if it's fertilized and we know if it's fertilized because it has what we call two

00:23:05.920 pronuclei. So DNA from the sperm and DNA from the egg. And then over the course of the next couple of

00:23:15.100 days, it divides into maybe six to eight cells. So about three days after fertilization, it's six to

00:23:22.720 eight cells. And then by five to six days, it's about 60 to 80 cells. And that's the stage where it

00:23:29.820 implants in the uterus. So five, six days after fertilization.

00:23:35.000 So with that said, now that we have a pretty good understanding of what all needs to happen for

00:23:41.480 fertilization and implantation, what is the biggest risk to that? And when does it cease to become a

00:23:49.280 zygote, by the way? I don't remember any of my terminology here. You have zygotes and blastospheres

00:23:53.580 or blastocytes? Yeah. A zygote, I think, is still a single cell that's fertilized and egg and sperm

00:24:01.040 combined. Then it starts to divide. We call it a pre-embryo. And then by two weeks, we call it an

00:24:07.640 embryo. But in IVF, we call it an embryo even in the first few days. Assuming that we have chromosomal

00:24:15.720 alignment. It's two weeks out. So we have a two-week-old embryo that is implanted. What is the

00:24:23.640 greatest risk that is faced by that embryo to coming to fruition as a fetus? In fact, going all

00:24:31.220 the way into the third trimester. So in other words, we've taken the biggest risk off the table,

00:24:35.480 which is aneuploidy. What are the other risks it faces? So once a pregnancy is established, you mean?

00:24:41.200 Yes. So if it's a normal embryo, chances are pretty good that it continues to turn.

00:24:47.520 So let's define normal. So normal at the macro level means chromosomally normal.

00:24:52.020 What else requires normality? Any other genetic issues that get in the way here?

00:24:56.300 There are other genes that play a role in embryo development. Those are less understood,

00:25:01.760 but there are certainly other genes involved. So you could have a chromosomally normal embryo that

00:25:06.820 fails to develop for other reasons. And then there could be uterine factors

00:25:11.160 that also play a role. So an embryo may implant, but if there's some structural abnormality,

00:25:17.940 for example, in the uterus, maybe that pregnancy can't continue and may result in a miscarriage.

00:25:24.000 Got it. Okay. So let's talk about a patient that comes to you. They're going to say,

00:25:28.960 we're having difficulty conceiving. What are the questions you have to render the diagnosis of

00:25:35.000 infertility, meaning we need some intervention versus, hmm, you just need to make a few adjustments

00:25:43.160 in something and I'm not willing to put the label of infertility on? Would that be the first

00:25:49.800 bifurcation in thinking?

00:25:51.560 Yeah. We want to take a full medical history, both partners, if it's a couple, and that includes

00:25:57.560 medical history, reproductive history, psychosocial history, sexual history. All those things are

00:26:03.040 important. Lifestyle factors. We ask about all those things. And the definition of infertility

00:26:08.720 is trying for about a year. So unprotected intercourse for about a year without success.

00:26:14.040 That's the medical definition of infertility. But we start our testing after a year in women who are 1.00

00:26:22.020 less than 35. And after six months, if a woman is older than 35, even though it may take longer to

00:26:29.140 get pregnant if you're older, if there's something wrong, you kind of want to know about it sooner

00:26:34.020 rather than later. So if a couple female partners over 35 and they've been trying, having time 1.00

00:26:39.900 intercourse at the right time and still not pregnant, then we would initiate some preliminary

00:26:45.180 investigations. On the female side, what's most important usually is we want to ask about the 1.00

00:26:51.020 woman's menstrual cycles. Are they regular? Is she tracking ovulation? Does it look like she's 0.83

00:26:56.540 ovulating, et cetera? The male side, we want to ask about sexual function. Have they had a semen

00:27:02.160 analysis? If not, we usually order one because we're interested in the sperm concentration,

00:27:07.560 the motility of the sperm, the shape of the sperm, those types of things.

00:27:11.860 One of the things I was very surprised by in the podcast that we did last week on male fertility was

00:27:17.240 how infrequently men are getting evaluated and how many missed opportunities. In other words,

00:27:23.560 how much wasted time is being generated because infertility is being assumed to be the responsibility

00:27:31.240 of the female. Responsibility might be the wrong word, but it's just assumed that, well, that's 0.86

00:27:34.760 more likely where it is. And so through no bad intention, the guy is not getting evaluated when

00:27:40.300 in reality the issue could have been with him all along and time is wasted.

00:27:44.100 Right. When you look at the data, it's about a third of the time it's a female factor, a third of the 1.00

00:27:48.300 time it's a male factor, and another third of the time it's some combination of male and female

00:27:53.000 factors. So yes, definitely one of the first things that we do is a semen analysis on the male

00:27:58.400 partner. And do you guys do that yourselves as well?

00:28:01.140 We do at the fertility clinic. Okay, great.

00:28:03.100 If there is an abnormality, we usually refer that male partner to a reproductive urologist

00:28:08.900 for further evaluation. But these days it's recommended actually that men, even if they're not trying

00:28:14.440 to get pregnant, sometimes assess their semen analysis. And because it can be a marker of 0.97

00:28:19.260 other health problems, just like a woman's menstrual cycle can be a marker of other health 1.00

00:28:23.940 problems. I should qualify that one year timeframe. If you have some reason to believe that you have

00:28:29.100 a fertility problem, I wouldn't necessarily wait a whole year and then go see a provider. If your 1.00

00:28:35.020 cycles are irregular, if you think you might have polycystic ovary syndrome or something, then you

00:28:39.520 definitely want to see somebody sooner than a year.

00:28:41.800 Is it possible to say anything about fertility rates changing over the past 50 years? Is there

00:28:47.500 any statement you can make on that?

00:28:49.100 Yeah, there's some data that seems to suggest that infertility rates are increasing over the

00:28:54.020 last several years. It's pretty common. I don't know if your listeners know, but about the lifetime

00:28:59.980 risk of infertility for each person is about one in six. So that's close to 20%. In the last few

00:29:06.240 years in the United States, it seems to be kind of a plateau of the prevalence.

00:29:10.320 Let me just ask a clarifying question, Paula. So if a woman gets pregnant in her 20s, but then in her 1.00

00:29:17.500 30s meets the criteria for infertility, would she be considered one of those one in six? 1.00

00:29:23.520 Yeah.

00:29:23.980 So we're going to say that the one in six means someone who wants to get pregnant at a certain 0.70

00:29:28.400 point in their life can't.

00:29:29.780 Exactly. Lifetime prevalence. Exactly. As far as the reasons for the increase in infertility prevalence,

00:29:36.040 it's not super well understood. Part of the reason is delayed childbearing.

00:29:39.980 I was just about to say, you could make it 100% if every woman decides to have a baby when she's 70. 0.78

00:29:46.200 By definition, you have 100% fertility.

00:29:48.740 Exactly. Yeah.

00:29:49.240 Exactly. Yeah. So women are waiting longer, of course, to start their families, 1.00

00:29:53.340 to pursue education, career, et cetera. Maybe they haven't found the right partner.

00:29:57.740 And so that definitely is contributing to increased rates of fertility. There's some

00:30:02.740 data that show that sperm counts are decreasing globally. It's a little controversial, but that

00:30:07.640 might be playing a role. It might be slight increased risk in sexually transmitted diseases

00:30:12.420 as well. So all those things are probably factors.

00:30:16.240 Is there an analysis that's tried to get at this by normalizing to female age? Because it seems to me 0.95

00:30:22.180 that if you could say, rather than make it lifetime prevalence, because that's going to be subject to

00:30:27.380 all the problems you've stated. But what if we just said, for women aged 28 to 32, 32 to 35,

00:30:36.180 like if we made narrow buckets of age, we could get a better sense of whether there's a true

00:30:42.400 infertility issue. Has that analysis been done? It's definitely been looked at by age. I don't know

00:30:48.140 the data off top of my head if it's been looked at by age over time, but definitely your chance of

00:30:55.140 infertility is higher if you're 40 compared to if you're 20 or even. But do we know if a 30-year-old

00:31:02.040 woman today has a higher rate of infertility than a 30-year-old woman 50 years ago? We think so, 1.00

00:31:08.440 but I don't know that data off the top of my head. If the answer there is yes, I don't know that it

00:31:13.600 would answer all our questions because it could still be explained by decreasing sperm count. It could

00:31:17.760 still be explained by increasing paternal age. This would be a very difficult analysis to do.

00:31:23.960 Right. Environmental factors as well. Our exposures are different now than they were 50 years ago.

00:31:29.940 Well, and then the question, of course, would be if this is an environmental reason,

00:31:34.340 what are the environmental triggers? Now, you mentioned STDs a minute ago. How do STDs and which

00:31:40.600 STDs play a role in fertility?

00:31:42.080 The ones most well understood are probably gonorrhea and chlamydia, which are very common

00:31:46.840 sexually transmitted diseases. And on the female side, those particular infections can ascend to the 1.00

00:31:53.240 fallopian tubes and cause scarring in the fallopian tubes, which then interfere with that process that

00:31:59.380 we talked about earlier, the egg and the sperm meeting and can lead to infertility.

00:32:04.780 And is that something that happens if it is left untreated, or is that something that's

00:32:09.000 easy to address with antibiotics if caught early?

00:32:12.080 I mean, if it's caught early, then it's usually treatable with antibiotics,

00:32:15.780 or there are some issues with antibiotic resistance, especially with gonorrhea. But

00:32:20.200 usually if you catch it early, it's treatable. But if it's late stage or it's unrecognized or

00:32:25.760 untreated, then it's more likely to ascend to the fallopian tubes where it usually cause fertility 0.87

00:32:30.400 problems.

00:32:31.580 How prevalent is gonorrhea today in the US?

00:32:34.000 I think it's pretty common. I don't know.

00:32:35.420 Really?

00:32:35.780 Yeah. Yeah. And certain populations is more common than others, but unfortunately. And there's a

00:32:41.860 number of reasons for that. Some of it is just lack of awareness and education about safe sex

00:32:47.800 practices, maybe less testing as well, especially we saw that during the pandemic for sure.

00:32:53.780 How does it present?

00:32:54.400 In women, usually with pelvic pain, fever, vaginal discharge, those are the most common symptoms.

00:33:02.900 And is it equally transmissible from male to female and female to male?

00:33:07.920 It's probably more transmissible from male to female.

00:33:11.740 Okay. And is it an STD where the person who has it knows, like if a male has it, does he know he has it?

00:33:18.380 Not always.

00:33:18.880 Presumably not if it's being transmitted this readily.

00:33:21.000 Yeah. Not always.

00:33:22.960 What about HSV? Does that factor into fertility at all?

00:33:26.580 Not as much.

00:33:28.020 And chlamydia, again, I apologize for my ignorance. I just don't remember any of this stuff since

00:33:32.320 taking the USMLE exams.

00:33:34.860 Tell me how chlamydia presents and how it impacts fertility.

00:33:37.640 The same actually. Yeah. Very similarly. So pelvic pain, fever, usually they're both present together.

00:33:44.440 And does it have the same pathology where it creates, it ascends the fallopian tubes and scars the tubes?

00:33:51.060 Yeah.

00:33:51.600 So worst case scenario, if a woman undergoes a severe infection with one or both of these,

00:33:56.620 it's not treated in time. She has completely scarred fallopian tubes. Is it still likely that

00:34:03.220 she could get pregnant through IVF? Are the eggs and uterus still preserved enough to... 0.97

00:34:08.440 Yes. Yes. It doesn't usually affect the uterus or the eggs or the ovaries. Now she may not know

00:34:15.000 that she has blocked tubes until she starts trying because you wouldn't necessarily feel

00:34:20.000 different if your tubes were blocked. So one of the tests we were talking earlier about

00:34:24.060 what testing we might do in addition to a semen analysis and getting a menstrual history,

00:34:28.720 et cetera, is we usually do an x-ray test. It's called a hysterosalpingogram or HSG for short.

00:34:34.860 And it's done specifically to evaluate whether or not the tubes are open.

00:34:39.540 So are you just injecting contrast? I assume you do this externally. You go into the cervix,

00:34:44.740 into the... You just inject dye and take an x-ray.

00:34:47.060 Exactly.

00:34:47.800 And you're looking for how smooth... And so tell me,

00:34:49.940 what does a normal fallopian tube look like on that test?

00:34:52.720 So first the dye... So it's done in radiology facility, usually by radiologists, although some

00:34:58.440 gynecologists do this test as well. But usually it fills up the uterus, so you can also see the uterus. 0.94

00:35:03.360 And then the tubes are kind of like these wire-like...

00:35:07.480 What's the diameter of a normal fallopian tube in that setting?

00:35:10.780 Less than a centimeter. Yeah.

00:35:12.380 That's pretty big.

00:35:13.440 Yeah. The whole tube, but the actual opening...

00:35:16.120 No. Yeah. How big is the lumen?

00:35:17.960 Microns.

00:35:18.900 Oh, wow. Okay.

00:35:19.720 Or millimeters. I don't know. Exactly. But you can see it. Definitely see it on x-ray and you can see...

00:35:24.620 Well, if you can see it, it's probably a millimeter or more than not a micron.

00:35:27.120 Yeah. For sure.

00:35:27.580 Yeah. Okay.

00:35:28.120 And then the dye is filling up the tubes and then spilling out the tubes. So you can see that process.

00:35:33.780 Right. The ovaries are not visualized because of the finger-like projection. So it's actually

00:35:37.640 spilling dye into the peritoneum at this point.

00:35:39.500 Right.

00:35:39.900 Okay. Based on that visual inspection, a trained radiologist and GYN can say,

00:35:46.100 that is smooth, that looks great, versus that is jagged and or obstructed.

00:35:51.300 Right.

00:35:51.460 Now, if it's obstructed, I assume that the woman has a much bigger problem, which is every month, 1.00

00:35:59.380 one of those eggs comes out, it's not getting past the point. Does it just atrophy and get

00:36:04.860 reabsorbed?

00:36:05.400 Yeah.

00:36:05.740 I see. So it wouldn't necessarily cause pain.

00:36:07.460 No. No.

00:36:08.220 By the way, we didn't talk about this earlier. We took it for granted. This is happening with

00:36:11.980 two separate sides.

00:36:13.500 Yeah.

00:36:13.700 Right. And it's just mind-boggling to me that there is one that is being selected and the

00:36:18.380 one that's happening in one side, somehow that signal is making it to the other side

00:36:22.160 to say, you can't do it this month.

00:36:23.760 Right.

00:36:24.100 How does that happen?

00:36:24.980 Who knows? We don't know.

00:36:26.160 We have no idea how that happens.

00:36:28.060 No idea. Something to do with the receptors on the eggs and particular hormonal milieu,

00:36:33.520 maybe there's some nerve that plays a role. We have no idea actually, but it is on average

00:36:40.780 50% from one side and 50% from the other side.

00:36:44.300 And it's a coin toss.

00:36:45.660 Right. And it's not necessarily alternating, but it's on average.

00:36:49.140 Right. It would be like heads is left, tails is right. If you throw it for enough times,

00:36:53.940 it's 50-50, but not necessarily back-to-back.

00:36:56.520 Exactly.

00:36:57.600 This is mind-boggling to me.

00:36:59.900 Yeah. It's fascinating.

00:37:00.580 It's mind-boggling if it were just one ovary, but the fact that these things are physically

00:37:04.880 a foot apart, not a foot, but half a foot apart, and some signal is transmitted,

00:37:10.780 in this woman's body.

00:37:12.100 Yep.

00:37:12.540 I mean, it's-

00:37:13.340 Yeah. Yeah. And we don't quite understand it.

00:37:15.640 That's incredible.

00:37:16.660 Yeah. Or whatever that egg that's being selected somehow develops the appropriate receptors

00:37:25.140 or whatever that only it can respond to the hormones. It's not necessarily signaling to

00:37:31.400 the other ones, but it's something is happening to that one that's being selected that's making

00:37:35.720 it the so-called dominant ballicle for that cycle.

00:37:39.040 Yeah. I suppose that's a more likely and plausible scenario is that something stochastically triggers

00:37:45.400 one and only one to develop a high enough receptor concentration for FSH or LH or something so that

00:37:53.240 it becomes the only one that, it's the only one that develops the radar.

00:37:56.460 Right. Now, of course, when we do in vitro fertilization, we're giving much higher doses

00:38:00.920 of FSH and multiple eggs are growing. So you can overcome this process and get multiple eggs to

00:38:07.320 grow, but we don't totally understand physiologically what makes just one grow each month.

00:38:13.660 Okay. Let's say you do the analysis and I assume if there's scarring on one side, but not the other,

00:38:21.360 would you intervene or would you just say, no, we're just going to take twice as long for one to get

00:38:26.140 through?

00:38:26.540 Yeah. There's still a chance to get pregnant. Although whatever process caused the scarring in 1.00

00:38:31.080 the one tube probably affected the other tube as well. So just because it's open doesn't mean that

00:38:36.680 it's functioning normally. Certainly can give it a few months of trying, but the other issue you have

00:38:42.880 to worry about is what we call an ectopic pregnancy. If that tube is not normal, if fertilization happens, 0.95

00:38:49.360 that embryo can implant in the tube. And that's kind of a very dangerous situation because obviously

00:38:54.500 the tube can accommodate a pregnancy. So usually that causes pain. And if it goes unrecognized-

00:39:00.740 It's a surgical emergency.

00:39:01.780 Yeah, exactly.

00:39:03.100 At how many weeks of gestation is a woman typically, because that's, I did my training in general

00:39:08.380 surgery. So that was one of the things we were always thinking about was ectopic pregnancies for

00:39:12.720 women presenting with abdominal pain. But I don't think I know the answer to this question, which is

00:39:16.380 how many weeks of gestation is a woman when she's showing up in the ER complaining of abdominal pain?

00:39:22.220 Usually about six to eight weeks of pregnancy.

00:39:25.840 Wow. Two months pregnant. 0.96

00:39:27.060 Right. Now remember we time pregnancy from like two weeks before ovulation. So by the time she 1.00

00:39:34.060 recognizes she's pregnant, she's already a month pregnant. So in the next month is probably the

00:39:38.940 most common time where those ectopic pregnancies present.

00:39:42.860 So when a woman has an ectopic pregnancy, can that fallopian tube be salvaged? 0.77

00:39:48.120 Sometimes. Sometimes if you recognize it early, it can be treated either medically or surgically,

00:39:53.820 and that tube can be salvaged. If you recognize it late and the tube ruptures, then oftentimes the

00:39:59.500 treatment is to just remove the tube. Plus, especially if it's not functioning normally.

00:40:03.660 Yeah. So when you remove that, let's just say it's a young woman, she's 25 years old.

00:40:07.860 You can't salvage the tube. You end up taking the tube. You're leaving the ovary.

00:40:11.220 Right.

00:40:11.720 So you still want her to have her endocrine system intact. What's happening to the eggs 0.99

00:40:15.420 that come out of that tube?

00:40:16.580 They just get released into the abdomen, the peritoneum, and resort.

00:40:20.120 So do you tell that woman your fertility rate just went down by 50%? 0.88

00:40:24.520 Yeah. She can still get pregnant if she has the other tube intact. But most of the time, 1.00

00:40:30.420 if the egg ovulates from the right, it's going to try and go down the right side. Although there

00:40:34.980 have been cases where you can ovulate from the right ovary and it can travel down.

00:40:39.240 It makes its way over to the other fallopian tube.

00:40:40.600 Makes it way over there. Yeah. It's rare, but it could happen.

00:40:43.700 What are the risks for ectopic pregnancy besides former STDs that lead to scarring in the tube?

00:40:49.000 Previous surgery, pelvic surgery in particular, like a ruptured appendix or something like that,

00:40:54.440 endometriosis can cause scarring of the tubes. Those are probably the most common.

00:40:59.440 Okay. Any genetic component to this? If your mom had an ectopic pregnancy or you- 0.88

00:41:03.900 Not that we know of.

00:41:05.640 So let's go back to our hypothetical case here. So woman comes in, let's just assume for the sake 0.99

00:41:12.260 of simplicity, the workup on her male partner, totally fine. His sperm are fine. The radiograph

00:41:19.380 shows that she has, at least to the eye, normal fallopian tubes. What's the next step in the workup?

00:41:25.380 So we want to assess her cycles and ovulation. So if she's ovulating regularly, then we call that

00:41:33.680 sort of unexplained.

00:41:34.780 And how do you know that she is? Is that determined by the fact that she has a regular period? Does

00:41:39.240 that alone tell you that?

00:41:40.180 Usually. Usually. It would be unusual to have regular periods and not be ovulating,

00:41:45.120 but it could happen.

00:41:46.400 How stringent is your definition for a regular period? It's not 28 days necessarily.

00:41:51.300 Not necessarily. Yeah. There's a range. It could be anywhere from like 21 to 35 days or so.

00:41:57.860 Wow. That's a pretty big range. Are you less concerned with the number of days of the cycle

00:42:02.500 and more concerned with the fact that whatever the days are, it's just repeating over and over again?

00:42:07.400 Yes. If you mean duration of the period-

00:42:09.480 Correct.

00:42:09.660 Yeah. That's not as important as how frequently the period is happening.

00:42:14.500 Even if it was 21 days, but it was always 21 days, that's better than it's 24, 28, 31.

00:42:20.600 There is some normal variations. Sometimes I'll see a patient and she'll say,

00:42:24.820 my periods are very irregular. Sometimes they're 26 days. Sometimes they're 32.

00:42:28.840 I consider that normal. It's not usually always 28 days or always 21 days. There's some normal

00:42:35.020 variation. Irregular would be you're skipping months or maybe you're getting a period every

00:42:41.080 three months or four months.

00:42:42.420 And what's happening in that situation in a young woman? 0.99

00:42:45.580 There are a number of different causes. Probably the most common is something called

00:42:48.720 polycystic ovary syndrome. It's a very common hormonal condition. We don't know exactly what

00:42:55.180 causes it. I feel like I'm saying that a lot about women's health. We don't know exactly what causes 1.00

00:42:59.460 it because we're not investing enough in women's research. 1.00

00:43:02.540 Why do you think that is? This came up on another podcast on HRT, which is another one of my big

00:43:08.200 rallying cries, which is how pathetic it is. Why do you think this is given how important a subject this

00:43:14.320 is? Political reasons. I think gender inequality, all kinds of reasons like that. 0.99

00:43:22.440 Do we have a sense objectively that there is a difference in this type of research or do we

00:43:27.140 think it's just that, well, maybe there's equal amounts of funding, but the innate problems associated

00:43:33.940 with the female reproductive system or female health in general are so much more complicated that 0.99

00:43:39.040 at equal funding levels, we're going to be far behind in our understanding.

00:43:43.440 Yeah. No, I think it's the former. You think it's abjectly-

00:43:46.140 Oh, there's good data that the funding for women's health research, it's like 10% of the overall NIH

00:43:52.140 budget, for example, it's very small. If you look at reproductive health, it's even smaller.

00:43:56.880 So it's a huge issue.

00:43:58.820 Let's talk about polycystic ovarian syndrome. So what's the prevalence of it in, let's say,

00:44:04.160 women aged, call it 15 to 30? 0.85

00:44:06.040 Yeah, super common. About 6% to 8% of women will have polycystic ovarian syndrome. Most common

00:44:11.580 symptoms are irregular periods, also evidence of high androgen levels, and that could usually

00:44:17.460 present with acne or excess hair growth. We call that hirsutism, obesity or being overweight. That's

00:44:25.220 also part of the syndrome.

00:44:26.680 The androgens are specifically just testosterone, just DHEA, DHE, all of the above?

00:44:32.140 Yeah, both, but typically elevated testosterone from the ovaries.

00:44:37.260 Is that the cause or the effect?

00:44:39.560 We don't know. We don't know, but it's definitely seen in almost all women with PCOS that they have

00:44:46.820 higher androgen levels.

00:44:48.620 And why is PCOS seemingly also highly associated with insulin resistance?

00:44:53.920 Again, we don't know exactly, but we think the androgens play a role. We think there might be some

00:45:00.420 genetic factors that play a role. I don't know that we understand why, but we certainly have

00:45:07.220 recognized in the last several decades that most women with PCOS also happen to be insulin resistant.

00:45:14.940 But we don't know the direction of causality?

00:45:17.620 No. We know that not everybody who's insulin resistant has PCOS, of course. Not all diabetics

00:45:23.160 are insulin resistant.

00:45:23.580 But we also know that some women with PCOS are not insulin resistant, correct?

00:45:27.600 Probably on some level they are, but they're able to compensate. And certainly it's more likely if

00:45:34.080 they tend to be overweight as well. So it's definitely multifactorial. And I guess it's like

00:45:38.360 we're treating PCOS now more like other complex diseases like obesity or hypertension, etc. There's

00:45:45.260 lots of things going on.

00:45:46.920 But based on what you just said, if there is any causality between them, it's more likely that the

00:45:52.620 PCOS is driving the insulin resistance than the other way around, given the number of women that 1.00

00:45:58.080 are insulin resistant who do not have PCOS.

00:46:01.000 Yeah, that's probably true.

00:46:02.160 So then the question is, what do we need to do to treat PCOS?

00:46:06.940 So it depends on the goal of the patient. So if they're trying to get pregnant, there's one set of 0.97

00:46:14.080 treatments. If they're not trying to get pregnant, but they have PCOS, then we usually focus on their 0.52

00:46:19.520 cycles because it's generally not a good idea to go too long in between cycles because what can

00:46:25.560 happen is the lining of the uterus can overgrow. If it overgrows too much, it can become what we 0.61

00:46:30.740 call hyperplastic, worst case scenario, cancer. So you definitely don't want that. So it's important

00:46:35.960 to be shedding that lining or to be on hormonal suppression so that that doesn't happen. If the goal

00:46:41.300 is to treat the hyperandrogenic symptoms like the acne and the hirsutism, again, hormonal treatments,

00:46:47.200 usually effective for that.

00:46:48.760 When you say hormonal treatments, you mean like spironolactone and things like that?

00:46:51.860 We usually start with birth control pills. Birth control pills, very effective for most

00:46:56.480 symptoms of PCOS. It'll regulate the cycles, decrease androgen levels, help with hirsutism and

00:47:02.040 acne, et cetera.

00:47:02.960 So let's talk about why. So a birth control pill is a high dose of a synthetic estrogen and

00:47:09.320 progestin. Correct.

00:47:10.880 That's given 21 days and then paused for a week, meaning you take it every day, but the

00:47:16.160 last week is a placebo. So is the reason that that helps with the hyperandrogenism because

00:47:22.180 it raises sex hormone binding globulin so much that it mops up all the excess testosterone?

00:47:27.300 Part of the reason. I'm impressed by your endocrinology knowledge. Yes, that's part of the

00:47:32.980 reason. And by the way, you can take it that way you described where you have a bleed every

00:47:37.320 month, but you don't have to. Many people take it continuously these days, so you don't

00:47:40.920 have a period at all.

00:47:42.400 But then doesn't that address the issue that you were talking about? Or does the synthetic

00:47:46.120 estrogen, the synthetic progestin offset the hyperplasia and then you don't care?

00:47:51.100 Right. When you take the combination of estrogen and progesterone, usually the lining becomes

00:47:54.780 quite thin.

00:47:55.320 Thin anyway.

00:47:55.700 You don't have to worry about it. Yeah. So two mechanisms of action. When you're taking

00:47:59.620 those high doses of estrogen and progesterone, it's suppressing the pituitary hormones, namely

00:48:04.220 the LH and FSH. But the LH is what drives the testosterone production in the ovary. So that's

00:48:10.480 one mechanism. And the other one is the one you described. So the estrogen component of the pill

00:48:15.260 will increase the sex hormone binding globulin so you have less free testosterone around. So again,

00:48:21.240 that will help with those symptoms we talked about.

00:48:24.500 Okay. So woman with PCOS doesn't want to get pregnant, just wants to reduce the androgen impact 0.99

00:48:32.700 and protect her uterus. A constant oral contraceptive is a great strategy. 1.00

00:48:39.240 Great strategy. Yeah. There are others. It could be a progestin IUD. That's a hormonally active IUD.

00:48:45.480 So there are a number of different ones. We're just taking progesterone every few months that usually

00:48:50.100 will help protect the lining, but probably won't decrease the androgen levels.

00:48:54.120 And how often do you place women who have PCOS also with insulin resistance on metformin? Do you

00:48:59.760 find that or any of the other diabetic agents to be particularly useful?

00:49:03.740 Occasionally. Yeah. And that's an important point because women, as we said, who have PCOS are 1.00

00:49:09.240 insulin resistant, which predisposes them to diabetes. So those women need to be screened periodically for 0.98

00:49:14.660 diabetes. And we commonly use metformin to either treat prediabetes or to try and prevent diabetes.

00:49:22.580 Does insulin resistance and type two diabetes independently impair fertility? All things being

00:49:28.940 equal, absent PCOS? That's a loaded question. Yeah. In some cases, I mean, there's some data that

00:49:34.860 shows that metabolic diseases or chronic diseases can impact fertility. Mechanisms, again, are unclear,

00:49:41.860 but probably related to both ovulation dysfunction and also endometrial receptivity.

00:49:49.520 Okay. So now I assume that's the easier way to treat PCOS is the woman who does not want to get 1.00

00:49:55.800 pregnant. So now let's talk about the woman with PCOS, but who is also trying to conceive. 1.00

00:50:01.860 What is your playbook? So we always counsel these patients as well. I should mention whether they're

00:50:07.580 trying to get pregnant or not, especially if they're overweight or obese, weight loss helps 0.98

00:50:11.180 with all the symptoms of PCOS. So healthy diet, lifestyle, et cetera.

00:50:15.760 And how much of a role are GLP-1 agonists playing in this now? How much more success are you having

00:50:20.720 with treating PCOS that way?

00:50:22.560 Yeah, increasingly. And they're very successful, as you know, for weight loss. And there have been

00:50:27.500 some studies on PCOS patients specifically, very effective.

00:50:30.900 Do you know any of those data? I'm not familiar with them.

00:50:32.580 Yeah. They work really well, just like they work in people with diabetes or people who with obesity

00:50:38.360 without diabetes. Problem is you can't get pregnant while you're taking them. And the current

00:50:42.480 recommendation is to stop for at least two months.

00:50:44.640 And pardon my ignorance, why?

00:50:46.140 Because we don't have any data on whether they're safe.

00:50:48.660 Yeah. So FDA is saying, I forget the FDA's classification for this. There's like A, B,

00:50:53.420 C, X or something like that for every drug?

00:50:56.200 Yes. I haven't looked for that one specifically, but I'm sure it's X because we have no data.

00:51:00.560 That's an important message for anybody listening. If you're trying to get pregnant,

00:51:04.420 you should not be on a GLP-1 agonist because we don't understand the impact of that.

00:51:09.220 Right. You can be on it pre-pregnancy. Just the recommendation is to stop for at least two

00:51:13.140 months. Now, having said that, there've been lots of, you may have read about,

00:51:17.180 azempic babies, like people getting pregnant on GLP-1. So there is a registry. And so far,

00:51:22.860 to my knowledge, there haven't been reported birth defects and that type of thing. But obviously,

00:51:28.540 we're talking about a small number. Yeah. That's an interesting point. And now

00:51:31.380 that you've mentioned that, I now recall hearing about that. So presumably, these are women who 0.99

00:51:36.620 have taken either semaglutide, trisepatide, and presumably they get pregnant.

00:51:41.640 Yes.

00:51:42.100 Either intentionally or not. So that's a very interesting registry to follow.

00:51:47.220 Right. Now, of course, once they find out they're pregnant, usually they stop. 0.94

00:51:50.120 They're usually counseled to stop.

00:51:51.120 Yeah. So we don't know what would happen if you continue. I don't think anybody wants to do that

00:51:55.180 study at the moment. Yeah. It doesn't make sense. Certainly don't want women who are 1.00

00:51:59.540 pregnant to not want to eat. Okay. Understanding that a woman who's got PCOS is going to be first 1.00

00:52:05.720 counseled to make these changes that effectively help her lose weight and increase her metabolic

00:52:11.040 health. Let's say she is somewhat successful, but still unable to address the concern.

00:52:17.840 Luckily, there are very good ovulation-inducing medications available. What we would typically

00:52:24.060 recommend for someone with PCOS to help them ovulate more regularly is a medication called

00:52:28.960 Letrozole. The brand name is Femara. And it's just a medication you take for five days in your

00:52:34.960 cycle. And then we can usually assess ovulation with ultrasound.

00:52:39.020 And what does it do?

00:52:40.400 Basically, it's a category of medication called aromatase inhibitors, which blocks the-

00:52:45.740 Conversion of testosterone to estrogen.

00:52:47.260 Right. Androgens to estrogen. That lower estrogen somehow triggers the pituitary to

00:52:53.720 increase secretion of FSH and LH. And that stimulates the ovary to, again, get one of those 0.53

00:53:00.540 follicles to grow. And is the reason you use something like

00:53:04.040 an aromatase inhibitor as opposed to clomiphene or HCG is just that it's a smaller nudge and

00:53:10.780 you're starting out with it?

00:53:11.780 No. We used to use clomid first line for PCOS, but then there was a study that came out several

00:53:17.660 years ago comparing the two and showed the pregnancy rates were a little bit higher with

00:53:21.560 letrozole. Clomid's perfectly good as well, but letrozole's better for PCOS. So if you have

00:53:27.220 access to letrozole-

00:53:28.460 That's very counterintuitive. If you think about it, when you take an aromatase inhibitor,

00:53:33.280 you're going to lower estrogen, but not, I mean, I guess it depends on the dose. I guess I'm

00:53:38.020 trying to think of like an astrozole, which I'm more familiar with than letrozole.

00:53:41.780 I suppose if you took a milligram of an astrozole every day for five days, you would drive estrogen

00:53:48.240 down. But I didn't think that that reduction in estrogen would lead to a high enough amount

00:53:55.400 of gonadotropin releasing hormone, which is effectively what has to be happening. It has

00:54:00.220 to be going up to drive the secretion of LH and FSH.

00:54:03.560 Right. Yeah.

00:54:04.860 Yeah. Again, that's still counterintuitive to me. I would just think that giving 50 to 100 milligrams

00:54:09.360 of Clomid would have a much bigger impact on that.

00:54:12.440 Yeah. It also works, but when they compare them, yeah. Randomized control trial, head-to-head

00:54:17.480 comparison show the pregnancy rates were better for some reason with the letrozole compared to Clomid.

00:54:22.740 Okay. And does it matter when in her cycle she takes the letrozole?

00:54:28.640 Usually it's recommended from day three to five. With the first day of full bleeding,

00:54:33.460 we call that day one.

00:54:34.740 What if the whole point of this is she's not having her period? How do you then time it?

00:54:38.100 We induce a period, not a real period, but we induce a withdrawal bleed by giving progesterone

00:54:43.040 typically.

00:54:43.960 Okay. So you give a woman progesterone and then by withdrawing the progesterone,

00:54:49.580 that's so cool. You guys are so manipulative.

00:54:52.820 I know.

00:54:53.420 How much do you give? 200?

00:54:55.420 No, five to 10 milligrams of medroxyprogesterone acetate, or you can give

00:55:00.300 micronized progesterone for about seven to 10 days.

00:55:03.720 Only five to 10 milligrams of micronized progesterone?

00:55:07.100 No. Micronized progesterone, 200 milligrams.

00:55:09.980 Okay. Yeah. So you give the full party dose of micronized progesterone for five days.

00:55:13.440 Yeah. Medroxyprogesterone acetate, five to 10 milligrams.

00:55:16.180 So then, by the way, do you have a preference for MPA versus micronized?

00:55:19.580 No, not really.

00:55:20.460 Okay.

00:55:20.860 Because it's such a short course.

00:55:22.440 So you give the full dose of endometrial progesterone for five days. The second you

00:55:27.820 take it off, it's the withdrawal of progesterone that causes the lining to shed. And then we

00:55:33.080 call that day one. And then you said on day five, we go ahead and start ripening the follicle

00:55:37.720 with the aromatase inhibitor.

00:55:39.180 Three to seven. Yeah.

00:55:40.220 Day three to seven.

00:55:40.720 For five days.

00:55:41.320 Wow. Very cool.

00:55:42.560 Yeah. And then we usually do an ultrasound around day 12-ish. You could see one of those follicles

00:55:48.460 starting to grow. Not all patients will respond. So sometimes we have to increase the dose or

00:55:53.560 sometimes we have to try a different medication. But most patients with PCOS will respond to that

00:55:58.080 medication.

00:55:59.140 Would you say that every single woman out there with PCOS who wants to get pregnant has access 1.00

00:56:04.280 to a doctor that understands what you just described and can do that for her? Or do you worry that too

00:56:11.140 many women are being shunted to IVF too soon without an attempt at something like this? 1.00

00:56:17.260 I definitely think there are probably not enough people who totally understand management of PCOS,

00:56:22.280 especially in the context of fertility treatment, for sure. And even in the context of non-infertility

00:56:29.600 treatment, often what I hear from patients is they had irregular periods. Somebody told them to start

00:56:34.800 go on the birth control pill. They never told them why. They didn't even know what they had PCOS.

00:56:40.320 Happens to be the correct treatment. So great. But they've gone years now not understanding that

00:56:45.940 they have PCOS and the implications of that, which as we talked about, there are metabolic

00:56:50.100 implications, et cetera. So that's a problem. But once they want to become pregnant, very few 0.97

00:56:57.000 general gynecologists are set up to be able to treat patients with either Clomid or Letrosol. Some of

00:57:04.200 them do, but it's not like a fertility clinic with reproductive endocrinologists because we're set up to do

00:57:09.580 monitoring seven days a week and that type of thing. But not everybody has access to a fertility

00:57:14.860 specialist. Very dependent on where you live. A little bit better now with telehealth, but still.

00:57:21.280 Do you have to do the sonogram when you're doing this?

00:57:24.340 You don't have to, but you want to know whether the woman's responding, meaning that she's actually

00:57:29.820 ovulating. There are other ways to assess that. If she gets a period at the right time,

00:57:34.500 then she's probably ovulated. Or if she gets pregnant, of course. Or you can check a progesterone

00:57:38.480 level in the luneal phase, the second half of the cycle. And if it's elevated, she's probably ovulated.

00:57:43.860 We just happen to use ultrasounds just easier.

00:57:47.620 And how much of what you're describing is covered with typical health insurance?

00:57:53.060 Kind of depends where you live. In the United States, it's very state dependent. Some states

00:57:57.520 have infertility insurance mandates where your employer's insurance policy has to provide

00:58:03.200 infertility, diagnostic, and treatment. But many states, infertility is not covered. Or they might

00:58:09.120 just cover the testing portion, but then not cover the treatment portion. So that's a huge problem.

00:58:15.180 You're in Oregon.

00:58:16.000 I'm in Oregon.

00:58:16.940 What is the state there?

00:58:18.380 We don't have an infertility insurance mandate yet, although we're working on it. It's actually

00:58:22.920 a bill in session, this regular session now that we're trying to get passed. Because infertility is

00:58:28.280 a disease like every other disease. And we think it should matter where you live. You should have access

00:58:33.420 to the appropriate treatment. So in our state, it kind of depends on your employer and whether they

00:58:40.380 provide that particular insurance coverage.

00:58:43.680 And so if a person has health insurance that does not cover reproductive care,

00:58:48.880 how much would be the cost of what you just described, the out-of-pocket cost?

00:58:52.780 Yeah. So letrozole and Clomid are just oral medications.

00:58:55.840 Yeah, they're cheap drugs.

00:58:56.740 They're pretty cheap. Yeah. But then you add the ultrasound monitoring,

00:58:59.860 that could be another $300 if you're paying out-of-pocket. And then if you're doing

00:59:03.900 intrauterine insemination, for example, which we haven't talked about.

00:59:07.180 No. Let's just say just what we talked about is still a really cheap treatment, right?

00:59:10.920 Relatively. Yeah. It's a few hundred dollars a month. For some people, that would be a lot.

00:59:14.420 But relative to what we're about to talk about, this is still well within the purview of out-of-pocket.

00:59:19.700 For sure. Compared to- Compared to what's coming. Yeah. For sure.

00:59:23.300 And so you kind of alluded to it, but I'm guessing you're saying, look, we would give this three

00:59:27.200 tries. Would that be a fair assessment? Usually. Yeah.

00:59:30.480 So we'd go through three consecutive cycles of this. It's interesting. So there's two ways that

00:59:36.180 this treatment could fail. The first is each time we did the ultrasound, we just didn't see an egg.

00:59:42.560 Right. Not responding.

00:59:43.920 We were not responding to the follicle stimulation.

00:59:46.840 Right.

00:59:46.960 So let's talk about what the implication is there. Alternatively, you could say,

00:59:50.900 God, three out of three months, we actually got ovulation, but we didn't get fertilization.

00:59:56.740 If you were three months of that, I assume in parallel, you're doing the male workup because

01:00:02.860 nothing would be a greater crime than going to all that trouble. And then you figured out the sperm

01:00:07.620 was the problem. But let's assume you have that box checked. Would you be more inclined to continue

01:00:12.180 that treatment for another three to six months?

01:00:14.440 Yeah. Yeah. And someone who hasn't been ovulating, they haven't tried for a year even.

01:00:19.120 They haven't even met the criteria.

01:00:20.240 Right. Exactly. So there's nothing magic about three months, but that's at least a check-in point

01:00:25.320 where we say, hey, do we continue doing this or do we move on to something else? So if it's a young

01:00:30.700 person and this is like the first time they're ovulating in their life, then yeah, we give them more

01:00:35.680 time on a less invasive treatment, less expensive treatment. If they're like 38, 40, we probably

01:00:42.420 move on to something else.

01:00:43.740 Okay. So let's go to the first case I described. So you get no ovulation. Okay. Three times,

01:00:50.480 no ovulation. We're not going to waste her time anymore, but she's still young. So what's your

01:00:54.580 next step in the algorithm?

01:00:56.040 Typically, so assuming we've tried higher doses and different medication like Clomid or whatever,

01:01:01.080 still not responding, then we typically move on to a class of medication called gonadotropins or

01:01:06.640 essentially FSH or follicle stimulating hormones, same hormone.

01:01:10.560 Not LH. You don't give HCG directly?

01:01:12.720 It's a little bit of combination. We do eventually give HCG to trigger ovulation. So we could either

01:01:18.660 use those medications with either timed intercourse or intrauterine insemination or with IVF. That middle

01:01:27.140 option with timed intercourse and intrauterine insemination has kind of fallen out of favor

01:01:32.540 a little bit because those medications are very expensive, acquire a lot of monitoring. Success

01:01:38.500 rate with IUI or timed intercourse is much lower than IVF. So we usually skip that and go directly to IVF.

01:01:46.640 Okay. If you are going to use FSH and LH, give me a sense of cost. What dose are you using of HCG?

01:01:54.560 So if the plan is just for timed intercourse, intrauterine insemination, we use maybe one to three

01:02:02.200 ampules of FSH and 75 units. The whole cycle, if you include the monitoring, the IUI, et cetera,

01:02:09.500 could be like $3,000 or $4,000. So you can see-

01:02:12.760 Now we're a big step up.

01:02:13.760 Yeah. After a few cycles, it's almost the same cost as an IVF cycle. So you're like better off,

01:02:19.520 especially if the patient wants to have, or the couple wants to have more than one child.

01:02:24.180 The advantage of IVF is you can freeze embryos. So if you want to have two or three kids,

01:02:28.860 might as well just do IVF and bank those embryos because otherwise you're going to have to do the 0.99

01:02:33.740 same thing all over again for your second kid or your third kid.

01:02:36.880 Yep. I see. So basically intrauterine insemination has largely fallen out of favor.

01:02:43.560 Does that also mean the cost of IVF is coming down? Is that also making it more attractive?

01:02:47.520 No. So IUI is very common still.

01:02:51.080 I see.

01:02:51.600 But we do it, we were talking specifically about the patient with PCOS-

01:02:56.220 Who's not ovulating.

01:02:57.000 Right.

01:02:57.340 Got it.

01:02:57.820 But otherwise, if you have a patient who is ovulating and has maybe unexplained infertility

01:03:03.720 tubes are open-

01:03:05.020 Yeah, yeah, yeah. In this case, you don't have to use a hormone to make her ovulate. You just need 1.00

01:03:09.600 an ultrasound, which is relatively cheap to know when she's going to ovulate.

01:03:13.400 Yeah. We still use the medication though because we super ovulate. So normally,

01:03:17.440 you just make one egg. So when someone's already ovulating, the goal of the fertility medications

01:03:21.980 is to get them to release more than one egg. So two eggs, three eggs, more eggs around,

01:03:26.680 higher chance that one of them is going to be normal and one is going to fertilize.

01:03:29.840 What does the graph look like of number of eggs versus probability of twins, triplets, etc.?

01:03:38.180 That's one of the downsides. So the risk of multiples with the oral medications like Clomid

01:03:44.660 or Letrozole is about 5% to 8%. So not super high, but definitely higher than patient were to conceive

01:03:51.320 without medication. So that's something we counsel them about. But it's very common as a first-line

01:03:56.920 treatment to do oral medication with IUI, even in the context of normal sperm, I would say,

01:04:02.660 although it's more important, of course, if there's a male component. And then if that didn't

01:04:07.580 work in three cycles, then move on to IVF.

01:04:11.300 And with the injectables, what is the risk of multiple pregnancies?

01:04:15.880 Much higher, 25 to 35%.

01:04:18.260 And how many eggs are typically...

01:04:19.920 It depends on the dose of the medication. So of course, when we're doing IVF, we want a lot of

01:04:26.420 eggs. So it's 10 to 15 eggs. But yeah, but if we're doing IUI, it could be like three to five eggs or

01:04:32.540 it depends on the dose and depends on the age of the patient, etc. So what's fallen out of favor is

01:04:37.800 injectables with IUI. We don't do that very much.

01:04:41.020 Got it. Makes sense. Back in the day when every time you were in the grocery store and you saw the

01:04:45.740 cover of the National Enquirer and there was like, this woman just had 47 babies. Like what the hell was 0.90

01:04:50.660 going on in those eras?

01:04:52.220 I think in the early days of IVF, well, even before IVF, when people just had access to injectables

01:04:58.500 and IUI, most of the multiple pregnancies were not from IVF, but from injectables and IUI.

01:05:05.360 Because literally there were women having eight and nine babies at a time. 1.00

01:05:08.580 Yeah. That famous octopolis case, I think that was actually an IVF case. So in the early days of

01:05:15.100 IVF, when IVF was not very successful, we had to transfer many embryos to get decent pregnancy rates.

01:05:21.940 And some of the time, more than one would take. So the pregnancy rates were the multiple pregnancy

01:05:27.000 rates. In that situation, they would have transferred eight and all eight took?

01:05:30.520 Yeah. I'm not saying it was the right thing to do, but that's what happened. One can split into two,

01:05:35.280 but in that particular case, more than the recommended number were transferred. So now

01:05:39.800 they're very strict guidelines from the American Society for Reproductive Medicine, which is our

01:05:44.820 professional organization, that almost always we're transferring just one embryo these days.

01:05:50.380 Unless a couple says, I'd actually like to have twins.

01:05:52.700 We kind of discourage that.

01:05:53.980 Why?

01:05:54.600 Because twins are riskier. They're riskier for the babies and for the mom.

01:05:58.800 Riskier in an IVF setting?

01:06:00.520 No, they're just riskier in general.

01:06:02.800 Are IVF twins, do they pose any more risk to either fetus or mom than naturally conceived twins?

01:06:08.300 Yes. There is some data that would suggest that IVF pregnancies are more complicated,

01:06:13.120 have a higher risk of complication than spontaneous pregnancies. We don't know exactly why if it's the

01:06:18.480 IVF or the fact that people who need IVF have underlying conditions that may predispose them to some

01:06:24.820 of these complications. Overwhelmingly, the data is reassuring that pregnancies do fine,

01:06:29.120 and the babies do fine. But we definitely know that twins, whether you conceive them spontaneously

01:06:33.900 or with IVF, the risk of almost every pregnancy complication is going to be higher.

01:06:39.980 So this is the risk of preeclampsia, HELP syndrome, blood clot, like anything that is a risk?

01:06:45.940 Hypertension, hemorrhage, yes. Need for a C-section, all those risks. Premature delivery,

01:06:51.920 all those risks are increased. So we don't intentionally like to produce twins,

01:06:55.740 although it happens sometimes, obviously. Okay. Boy, this is fascinating stuff. So

01:07:01.980 I'm just trying to take this in some sort of thoughtful order. Should we now move to IVF,

01:07:06.880 or do you want to say a little bit more about IUI? We haven't really talked directly about IUI.

01:07:11.180 By the way, I don't know what it is about when people say turkey baster, it makes me cringe like

01:07:15.760 that. It's just such a gross image to me. So I am deliberately not going to say it other than that

01:07:21.660 a moment ago that I just said it, but just so that people know what we mean by intrauterine

01:07:25.960 insemination, just to be clear, you are not using a turkey baster. Definitely not. Okay. Thank God.

01:07:31.800 Most disgusting image. I don't know why I get so grossed out by that. So can you explain how IUI

01:07:38.500 is done? We've already said that with IUI, you largely favor an oral preparation. Usually, yeah.

01:07:46.000 Okay. That means you're using an oral set of hormones so that the woman doesn't have a massive 1.00

01:07:53.080 proliferation of follicles. So the male ejaculates, do you want fresh semen or do you care if it's 0.99

01:08:00.000 frozen? What's the difference in success? Same. We have single women as well and female 1.00

01:08:05.620 same-sex couples who would also be doing donor insemination in that case.

01:08:10.360 And we don't see any difference between fresh semen and frozen semen?

01:08:14.180 No. Assuming the sperm is normal. Assuming the sperm is identical.

01:08:16.860 Yeah. Yeah. Exactly. So the indications for IUI would be those scenarios. I mentioned single

01:08:21.960 women, same-sex couples, or if there's a couple with unexplained infertility, you just can't find

01:08:27.600 a reason. So you just want to try and optimize their chances. Or if there's a male factor, right? So if

01:08:34.160 there's lower sperm count or lower motility, the idea with IUI is that the female partner would 1.00

01:08:40.260 take fertility medication to increase the number of eggs. She would track her ovulation. When she's 0.92

01:08:45.700 ovulating, she would come to the clinic. The male partner would come to the clinic, produce a sperm 1.00

01:08:49.860 sample. We process the sperm, which is basically collect the best sperm in a small volume, and then

01:08:56.460 place that sperm directly into the uterus through the cervix. 0.63

01:09:00.420 The problem that you're able to overcome on the sperm side would be number and motility. 0.55

01:09:07.740 Yeah. Or morphology. Like any abnormality in the semen analysis, as long as it's not very

01:09:13.220 chromosomal. So if the sperm are too few, they don't move well enough. If they're defective in most ways...

01:09:21.200 IVF. More specifically, ICSI, which stands for intracytoplasmic sperm injection, where we actually

01:09:27.180 take a sperm and inject it directly into an egg. So for severe male factor, that would be the

01:09:32.480 recommended treatment. But if the sperm's a little bit low, but it's not too bad, then IUI, we would

01:09:38.180 try a few cycles of that first.

01:09:40.020 Okay. So when in the woman's cycle, how many days before she ovulates do you want to inject those

01:09:48.300 sperm into the mouth of the uterus? 1.00

01:09:51.360 Essentially the day she's ovulating.

01:09:53.460 So this is interesting to me because one of the things that I took away from the discussion

01:09:56.720 with Paul last week was that if you look at the probability distribution curve of when

01:10:03.240 a pregnancy occurs, the ejaculate enters the uterus prior to ovulation. You have a, I forget

01:10:10.140 what he said, 80% of pregnancies occur when the sperm are there prior to ovulation. And I

01:10:17.660 could be wrong on this. I've already forgotten. I think only 20% occur post-ovulation. So the tail

01:10:22.640 falls off much quicker.

01:10:23.900 Yes. It is true that if there's sperm around prior to ovulation, it can hang around for a while

01:10:30.920 because it lives two to three days or so. Whereas the lifespan of the ovulated egg is much shorter.

01:10:37.740 So based on that, wouldn't it make sense to put the sperm in prior to ovulation? Or is it just too

01:10:43.360 risky to try and anticipate when that is?

01:10:45.460 If it's a stray couple, we'll tell them to also have intercourse every couple of days around the

01:10:50.360 time of ovulation. But the pregnancy rates in these probably back early studies that have looked at

01:10:55.740 this show that probably the highest pregnancy rate if you do the insemination on the day that you think

01:11:02.280 the patient is ovulating.

01:11:03.940 And are you doing that with ultrasound?

01:11:05.040 Usually LH monitoring. So patient will either monitor her urine, LH. Remember LH goes up just

01:11:13.720 before ovulation. We typically also do ultrasound based on the size of the follicles. We sometimes

01:11:19.600 trigger ovulation with HCG, which kind of simulates the woman's own LH surge. So if you want to be

01:11:26.220 pretty precise.

01:11:27.080 How big a dose of HCG do you need?

01:11:28.800 Usually 5,000 units, which is...

01:11:31.580 Half a vial.

01:11:32.180 It's a lot. Probably more than physiologic. The purpose is to cause release of the egg,

01:11:38.080 and then we time the insemination to happen when we think the ovulation is happening.

01:11:43.360 Okay. Do you ever do the following? This is me just thinking out the box. Get the male to bank a 0.75

01:11:49.760 ton of sperm. Take weeks to get... Or if she's going to a sperm bank, if it's a same-sex couple, 1.00

01:11:53.760 but whatever. Just get multiple aliquots of semen. So on day one, insert. Day two, 0.93

01:12:01.320 insert. Day three, give 10,000 IU of HCG, insert. And then day four, insert. In other words,

01:12:09.460 cover your bases and just have lots of semen sitting around and then force the ovulation. 1.00

01:12:16.000 You could do that, or the couple could just up sex.

01:12:18.620 But we then introduce another variable, right? Which is, what if the semen... What if the count

01:12:23.700 is low enough? Because if he's ejaculating every day, you're not having a chance to fully rebuild

01:12:28.340 the supply. What if his motility is anything other than perfect? Or in the other case,

01:12:33.500 what if we're dealing with same-sex couples or a single mom? 0.95

01:12:36.440 Yeah. There have been studies looking at two IUIs compared to one. Specifically,

01:12:41.760 same-sex couples or single women show no difference. And remember, if you're paying out of pocket 0.98

01:12:46.440 for all these things, it has to be worth it. So at some point, even if what I proposed worked

01:12:51.140 better, it's going to approach the cost of IVF. Right. How much better? And is it worth another

01:12:57.060 $400 five days? Now your cost of your IUI cycle is all of a sudden $2,000. Yeah. So those are

01:13:04.860 practical considerations as well. So maybe this question is too broad, so feel free to partition it.

01:13:10.520 But if you look at all uses of IUI, what is the success rate? And feel free to, again,

01:13:17.260 divide that up into different cases. The pregnancy success rate really depends

01:13:21.440 on the age of the female partner. So if it's a young woman in her twenties, success rate might

01:13:27.920 approach success rate for natural conception, which might be 20 to 25% per cycle. If it's a woman over 0.99

01:13:35.140 35, might be 10 to 15%. If it's a woman over 40, might only be one to 5% per cycle. 1.00

01:13:42.940 Wow.

01:13:43.160 And that's because, again, it's all about the quality of the egg. So even though an egg is

01:13:48.080 released, maybe two eggs are released. If those eggs aren't normal, they're not going to fertilize

01:13:52.680 an implant.

01:13:54.120 Okay. So we've covered a whole lot of fertility treatments. It seems that the likelihood that

01:14:02.000 a woman who's undergone some of the things we've discussed that still ends up going down to the 1.00

01:14:06.460 IVF pathway is reasonably high.

01:14:08.780 Yeah. The majority of people don't need IVF. Again, it depends on the age of the female partner 1.00

01:14:13.160 specifically and what the problem is.

01:14:16.160 So let's just go sub 35.

01:14:18.220 Okay.

01:14:18.500 So of all women who present with defined infertility, which if she's under 35 means more than a year

01:14:25.560 of regular sex, no pregnancy, walk through the success rate of pregnancy by modality. So

01:14:33.880 under 35, infertility for a year, how many are successful with just an oral treatment absent IUI?

01:14:41.020 Again, sort of depends on what the cause of the infertility is. Is it unexplained or is it PCOS?

01:14:47.420 No, let's say unexplained.

01:14:48.440 Unexplained? Probably less than 50% will get pregnant with IUI and have to move on to IVF 0.67

01:14:56.020 because unexplained to me means either it's bad luck or more likely there's something going on

01:15:00.940 and we just can't figure it out. In those cases, almost always IVF is going to give you a higher

01:15:05.180 chance of success.

01:15:06.680 Oh, sorry. Yes. That I can understand for sure. I'm saying how many of them will need to get IVF?

01:15:12.640 Are you answering that question as well?

01:15:13.800 Yeah. That's what I was getting at. For PCOS, their problem was they just weren't ovulating.

01:15:18.440 So probably 80% of those people will get pregnant with just ovulation induction and IUI.

01:15:24.640 So hormonal therapy basically is addressing the problem. Got it.

01:15:27.600 If it's very severe male factor, probably IUI is not going to work. So it really kind of depends

01:15:33.260 what the etiology of the infertility.

01:15:35.600 And so now if we talk about, oh, age 35 to 45, and again, let's take PCOS off the table in this age

01:15:41.520 group. So let's just say we're talking 35 to 45 year old women, PCOS not an issue. And let's just

01:15:46.500 also assert male not an issue. That's been worked out. Unexplained infertility. So I guess now

01:15:52.240 technically you would call it six months of not getting pregnant would be sufficient. But what

01:15:57.200 percentage of women will get pregnant absent an IVF strategy?

01:16:01.960 So depends how long you do it for. So most of the time we're only doing it for three cycles.

01:16:07.540 Because like I said, it's not cost effective to do it for longer. So I would say in that age group,

01:16:15.000 probably the majority of women will likely need IVF if they are not successful after three months. 0.98

01:16:22.360 Theoretically, if you continue doing IUI, a lot of those people will eventually get pregnant. 1.00

01:16:27.120 But we tend to stop at three months.

01:16:28.880 Tell me at three months again, what percentage are going to be successful with three cycles?

01:16:32.840 In that age group?

01:16:33.740 Yes.

01:16:33.940 Unexplained infertility.

01:16:35.240 Unexplained over 35?

01:16:36.300 I don't know the exact number, but probably under 50%.

01:16:38.620 Okay. But that could be a third potentially.

01:16:41.880 Yeah. Because the success rate per cycle is something like in that age group, let's say 10 to 15%.

01:16:48.020 So it's-

01:16:49.260 So you go one minus that number times three, one minus that to the third power should be about 30%.

01:16:54.980 Exactly.

01:16:55.940 Okay. So now let's talk a little bit about IVF. First successful IVF baby, 1978, if my memory serves

01:17:03.320 correctly.

01:17:04.060 That's right.

01:17:04.680 Referred to as a test tube baby, which is kind of weird because I would imagine it was in a Petri dish,

01:17:09.360 not a test tube. But anyway.

01:17:10.900 Yeah. Yeah.

01:17:12.240 We've come a long way since then.

01:17:13.960 We have.

01:17:14.120 For historical context, I don't know anything about that girl,

01:17:17.660 but do you know anything about how that was done back in 1978?

01:17:21.440 Yeah. Actually, there's a recent docudrama out called Joy.

01:17:24.840 Is that her name?

01:17:25.480 Her middle name, I believe, is Joy.

01:17:27.160 Ah.

01:17:27.660 Yes.

01:17:28.080 Well, that's great.

01:17:28.900 Louise Joy Brown.

01:17:30.080 What's her name?

01:17:30.800 Louise Brown.

01:17:32.120 Louise Brown.

01:17:32.420 I believe her middle name is Joy.

01:17:33.660 Got it.

01:17:34.320 It's a movie about the first IVF success.

01:17:37.620 Oh, that's great.

01:17:38.420 Now, of course, they tried for many, many years before they had the first success.

01:17:42.380 These were two doctors.

01:17:44.020 I mean, maybe this is all in the docudrama and I can't wait to check it out, but what kind

01:17:47.140 of IRB approval was there? How much controversy was there around this? It must've been a huge deal.

01:17:51.400 Yeah. There was a lot of controversy. Like, this was very freaky. Yeah. Yeah. And this was done at

01:17:58.140 the time primarily for women with tubal factor block tubes. I think, I can't remember the exact

01:18:02.520 details of the couple, but I believe they had tubal disease. And IVF works great for tubal disease

01:18:08.080 because, of course, you're bypassing the tubes altogether.

01:18:11.260 Where was this done?

01:18:12.340 In the UK and Britain.

01:18:14.140 I didn't realize it wasn't done here in the US. So, tell me a little bit about technologically how

01:18:19.100 they accomplished it back then. Yeah. I think the first cases, they were actually doing surgery

01:18:24.880 under general anesthesia. Open surgery to harvest.

01:18:27.460 Or laparoscopic, I believe.

01:18:28.520 Yeah.

01:18:29.040 To retrieve the eggs.

01:18:30.860 Oh, wow.

01:18:31.420 And then they were combining the eggs with the sperm in the test tube, Petri dish. And then I think

01:18:38.260 they were transferring the embryo maybe back into the tube in those days or maybe through the cervix.

01:18:44.400 I can't remember the details, but yes, a lot of it has changed over the last 45 years or so.

01:18:50.760 Wow. Despite that success in 1978, what did it look like for the next 10 years from 1978 to 1988?

01:18:59.680 How prevalent was IVF? I guess, when did it get to the point where anybody who could afford it

01:19:04.820 could access it?

01:19:06.180 Much more recently. Yeah. The first IVF baby in the United States was born a few years later,

01:19:11.200 I think maybe 1981 or so in Virginia, I believe. It took probably many decades for it to become

01:19:19.020 commonplace throughout the world. So now most countries, you can access IVF. Not everybody

01:19:24.840 can access IVF, but in some countries more than others. But depending on how you look at it,

01:19:29.680 it's kind of new, kind of not, 45 years. But in medicine, that's relatively recent development.

01:19:35.080 And it's been only in the last maybe 20, 30 years that it's become standard.

01:19:41.140 Okay. So let's just walk through how IVF works and then we'll kind of dive into the ins and outs

01:19:44.880 of some of the nuances. So a woman comes to you, probably she's progressed through some layers of

01:19:49.860 treatment, but you've collectively come to the decision that this is hands down the best

01:19:54.040 opportunity, both for success and risk. So how does the treatment go?

01:19:58.820 So typically we do a bunch of screening tests on both partners. That includes some blood tests,

01:20:03.960 a semen analysis, an ultrasound to get some assessment of their egg number, the woman's

01:20:09.500 egg number. And then when the cycle starts, takes about two to three months to complete a cycle of IVF.

01:20:16.500 And when you say egg number, are you determining that through an AMH or through a physical examination

01:20:22.140 of the ovaries?

01:20:23.380 Both. So we do an ultrasound, we can count the number of follicles.

01:20:26.820 How small are these things?

01:20:28.060 A few millimeters.

01:20:29.980 And you have the resolution to see that on an ultrasound?

01:20:32.360 Yeah. And that gives you some sense of about how many eggs that particular patient will produce

01:20:38.560 with ovarian stimulation. And we use AMH as a hormone you mentioned.

01:20:42.380 Explain what AMH is and how it works.

01:20:44.180 Yeah. AMH is a hormone that stands for anti-malarian hormone. It's secreted by the

01:20:48.980 cells that surround the egg. So it tends to correlate with egg number. Doesn't tell you anything about

01:20:53.900 fertility or pregnancy rates or anything like that. Age is still the most important factor 1.00

01:20:58.040 in that sense. But it does give you an idea. Do you have a normal number of eggs for your age?

01:21:03.040 Just numbers. So two women that have the same number of eggs, if one woman has high quality 1.00

01:21:08.340 eggs, the other woman does not, they could still have the same AMH level on a blood test. 1.00

01:21:12.640 Right. If they're different ages, their success rates can be different.

01:21:16.560 Remind me of the range. So a prepubescent girl who has a billion, not a billion, but right, 0.97

01:21:22.020 a million eggs, but who is not fertile, does she have a high or low AMH? 1.00

01:21:26.700 She has a higher AMH. We tend not to use it in that age group because it's less reliable,

01:21:31.240 but a normal AMH would be about two. I think the unit is peak around per deciliter, I believe.

01:21:38.120 Less than one is considered low. So a woman who's older- 1.00

01:21:41.540 But what's the difference between a 16-year-old girl who probably could get pregnant if she 1.00

01:21:45.980 walked past a guy versus-

01:21:48.240 Versus-

01:21:49.140 That never happens, by the way.

01:21:50.660 Oh, okay, good. No, but if you have like a 16-year-old girl who is at the peak of her

01:21:54.980 fertility versus a 30-year-old woman who is still fertile, but has lost a step, like what's the 1.00

01:22:00.880 difference in AMH between-

01:22:01.960 Yeah, it's a very narrow range.

01:22:02.840 Okay.

01:22:03.240 So like above two, we consider that's probably normal reproductive age.

01:22:06.460 Above two is two effectively.

01:22:07.960 Okay.

01:22:08.020 Now it can be high too, and patients with PCOS, for example, have very high levels, but different

01:22:13.760 thing. But above two, that's usually good number of eggs. Less than one,

01:22:18.240 low number of eggs.

01:22:19.140 So this is kind of a binary test.

01:22:20.800 Well, not really.

01:22:21.680 You're not looking at, oh, this woman's 1.6, this woman's 1.7, this woman's-

01:22:25.740 No, no, not that.

01:22:25.960 Yeah. You're not looking at it like you look at a TSH or something.

01:22:28.240 Right, right. And the assay is also very variable, depends where you have it done,

01:22:31.580 whatever just gives you an idea. Is the egg number average for your person's age? More than average,

01:22:36.440 less than average. And it helps us because we can determine what dose of medication to use

01:22:42.040 during IVF. And we also can give expectation to the patient, you're probably going to make

01:22:47.200 five to 10 eggs, maybe not 15 to 20 and that type of thing. When she's ready to start the cycle,

01:22:53.260 everything usually starts with her period, depending on the age again. But usually the

01:22:57.300 patient starts on a couple of weeks of birth control pills. What that does is kind of suppresses

01:23:02.060 the ovaries because we want all the eggs to kind of grow at the same rate. Stop the pill, 0.97

01:23:06.240 then start the gonadotropins, which are the FSH.

01:23:08.760 Now you go injectable.

01:23:09.280 Yep. And they're injectable, just under skin kind of injections.

01:23:12.140 So meaning HCG and FSH.

01:23:15.040 Not an HCG, but primarily FSH with a little bit of LH. So you're on those for about eight to 12 days.

01:23:23.100 And then every few days while you're taking those medications, you have to come into the clinic

01:23:27.340 for ultrasound monitoring and estradiol levels, blood levels. And we can monitor how many follicles

01:23:34.680 are growing, how big they are, et cetera. Usually the medications are pretty well tolerated.

01:23:39.920 And what dose of LH and FSH is she injecting relative to what she would normally make? Is it

01:23:45.900 a 2X, 5X, 10X?

01:23:47.840 It depends on the age. Again, higher doses for women who are older, but much, much higher doses.

01:23:53.540 More than 10X?

01:23:54.340 Hmm. Maybe not. Maybe five.

01:23:57.180 Typical symptoms?

01:23:58.480 Most common, I would say, is bloating as the ovaries get a little more enlarged. 0.99

01:24:02.380 There's a small risk of something called ovarian hyperstimulation syndrome when the ovaries get

01:24:07.000 a little bit too stimulated, but that's exceedingly rare. There's signs that it's happening. We can

01:24:11.520 always back down on the dose. Sometimes the patient doesn't make as many eggs as we were hoping. So

01:24:16.300 sometimes we have to increase the dose or change the protocol, but usually we guess pretty right.

01:24:21.660 And then once the follicles are a certain size, that's how we know the eggs are mature. Because

01:24:27.140 of course we can't see the eggs on the ultrasound. You can only see the follicles that contain the

01:24:31.600 eggs. So then the patient gets HCG, which is another medication, which kind of simulates her

01:24:37.900 own LH surge. And the purpose of that medication, it causes the final maturation of the eggs. And if we

01:24:45.300 did not do an egg retrieval, she would release all those eggs. But of course we time the egg retrieval 0.95

01:24:50.580 to happen just before the woman ovulates. So that medication is very time sensitive.

01:24:55.840 And to be clear, were you only giving her FSH before or were you giving her LH as well?

01:25:00.420 A little bit of LH, but mostly FSH.

01:25:02.440 And why are you using LH versus HCG?

01:25:04.960 Just to simulate the physiologic cycle.

01:25:08.740 I didn't realize there was a difference appreciated by the body between them.

01:25:12.060 They're very similar. So we use HCG for, but the body of course doesn't have HCG until the

01:25:18.400 patient's pregnant, but it works well as a substitute for LH. 1.00

01:25:22.320 So there is synthetic LH out there as a drug?

01:25:24.720 Yeah.

01:25:25.100 Okay.

01:25:25.560 It's combined with, comes in as a combination drug.

01:25:28.920 With the FSH?

01:25:29.660 Yeah.

01:25:30.040 Got it. I see. So how do you prevent her from ovulating while you are giving her FSH and LH 0.99

01:25:39.760 and she is ripening multiple foliosos? How are you preventing an ovulation?

01:25:42.340 Good question. There's another medication that we give. It's called the GnRH antagonist. It

01:25:48.500 basically blocks the LH surge from happening until we cause it.

01:25:54.180 When you're giving her FSH, the LH that's attached to it is very, very low.

01:25:58.400 Right.

01:25:59.260 That will prevent an ovulation. 1.00

01:26:01.700 Yes. The antagonist will. Basically blocking the GnRH, which is another hormone.

01:26:06.460 I'm surprised that the fact that you're giving her so much FSH with a little bit of LH isn't

01:26:11.580 enough to suppress the GnRH. But anyway, clearly not, or you wouldn't be having to give her that.

01:26:16.720 Okay. So you give her a GnRH antagonist that basically puts a block between her hypothalamus 0.95

01:26:22.500 and her pituitary.

01:26:23.480 Right.

01:26:24.380 So then now you control the switch and the switch is in the megadose of HCG, which is an LH analog.

01:26:30.540 Do you harvest the follicles in the fallopian tube?

01:26:34.880 In the ovaries. So the egg retrieval happens two days after that HCG trigger.

01:26:41.580 Wow.

01:26:41.900 Yeah.

01:26:42.300 It would have taken two days.

01:26:44.120 36 hours specifically. So she usually takes it in the evening and then the retrieval.

01:26:49.220 The day after in the morning. Okay. So a woman comes into your office two days later and walk 0.99

01:26:55.320 me through this. So you lay her on a table, you've got an ultrasound on her ovary and you're

01:26:59.000 literally putting a needle in there.

01:27:00.340 Well, first of all, she's asleep.

01:27:02.620 Fully asleep or just local sedation?

01:27:04.560 Propofol. Yeah. So this is done in a surgery center typically or clinic with anesthesiologists,

01:27:10.660 is present, IV sedation.

01:27:12.820 It's like a colonoscopy or dental extraction or something.

01:27:16.480 All done vaginally actually using the ultrasound. And that day there's a needle that's guided

01:27:21.960 by the ultrasound that goes through the vagina into the ovaries. So we don't do transabdominal. 0.97

01:27:26.660 Dumb question. Don't you have a much straighter shot going through the abdomen?

01:27:30.460 Not really.

01:27:30.780 You just don't want to go through the peritoneum.

01:27:32.240 And there's a lot of stuff between the abdomen and the ovary. 0.51

01:27:35.100 So you can't just manipulate and move the bowel out of the way or something?

01:27:37.340 It's much easier through the vagina. They're sitting right there. 1.00

01:27:40.440 So again, just pardon my ignorance of the anatomy because again, I'm probably still locked

01:27:44.280 into the image of the ovaries being like this. But you're saying, no, Peter, the ovaries

01:27:49.260 are probably sitting right on top of the uterus. 0.97

01:27:50.880 Right on top of the top of the vagina. To the side of the uterus, you just stick a needle 1.00

01:27:54.740 on either side.

01:27:55.780 So literally out of the vagina, not even going through the cervix. 0.93

01:27:58.820 Yep.

01:27:58.980 That still strikes me as a very delicate, complicated procedure.

01:28:03.160 I mean, it's a surgery. Yeah. Relatively minor type surgery.

01:28:08.220 How much do you have to dilate the vagina? What I'm thinking about is how do you get 1.00

01:28:10.920 your hand in there to guide the needle?

01:28:13.140 You don't have to get your hand in there. Yeah. You should watch a YouTube video, but

01:28:16.700 it's just the ultrasound probe and there's a needle guide.

01:28:20.280 Is the needle guide inside the probe or alongside?

01:28:23.460 Alongside.

01:28:23.980 Okay.

01:28:24.640 And the needle, it's a long needle, right? So your hand's not in the vagina. 1.00

01:28:28.980 It's 16 and it goes through the vagina. You're doing this under ultrasound guidance. You can 1.00

01:28:34.420 see exactly.

01:28:35.560 But somebody else is obviously manipulating the ultrasound for you.

01:28:38.380 No, no. You have it in your hand. It's a vaginal ultrasound. 0.94

01:28:40.320 Oh, that's right. That's right. Yeah, yeah, yeah.

01:28:41.880 So you're doing both. So you're looking where you are with the ultrasound and you're using

01:28:46.120 the needle to puncture the ovary, get into the follicles. The needle is attached to like

01:28:51.840 a vacuum suction. And so the fluid and the follicles collected goes through the needle,

01:28:58.220 into the test tube. And then that test tube is handed off to the embryologist. They look

01:29:04.180 under the microscope and try and isolate the egg.

01:29:07.500 Now, I'm just so full of dumb questions here today, Paula. How do you prevent yourself from

01:29:13.000 sucking out 300 non-follicle eggs and ultimately destroy your long-term fertility risks?

01:29:20.760 Well, you only go into the large follicles, which are really the only ones you can see

01:29:25.940 on ultrasound. There's a gazillion of eggs in there, but you can't even see them.

01:29:29.720 And you're not running the risk of sucking up those eggs?

01:29:32.400 No. No, you're just going into the follicles.

01:29:34.780 How big is the ovary? 0.90

01:29:36.260 The ovary is a few centimeters at that point, but each follicle is about two centimeters,

01:29:41.460 I would say. And there might be 10.

01:29:42.920 Wait, wait, wait, wait. How is each follicle two centimeters?

01:29:46.100 In diameter.

01:29:46.660 But you said the ovary is only a couple of centimeters.

01:29:48.880 No, it's like maybe five, six, like a small plum or something.

01:29:53.200 Okay, wait a minute. So if you have a plum or a tangerine that is the ovary,

01:29:57.880 you're saying each follicle is two centimeters in diameter?

01:30:01.560 Roughly.

01:30:02.200 That's huge.

01:30:03.160 1.5 to 2.

01:30:04.380 I wouldn't have even thought it was one centimeter. How many follicles are in there?

01:30:08.180 On average, we get 10 to 15. So maybe the ovary is bigger. 0.87

01:30:12.920 Maybe it's more like an orange.

01:30:13.620 I'm thinking more an unstimulated ovary is more like a plum. When it's stimulated,

01:30:18.040 more like a grapefruit.

01:30:19.320 Okay. I see. So you have really good resolution of where the follicles are.

01:30:23.420 Oh, yeah. Yeah.

01:30:23.800 Okay. So you're not running the risk of sucking everything out of the ovary.

01:30:28.080 No. And we're just getting fluid, right? We're not touching tissue of the ovary,

01:30:32.560 just the fluid and the follicles.

01:30:34.700 It's only a 16-gauge needle. Does that mean you're

01:30:38.080 puncturing the follicle?

01:30:40.020 Each follicle, yeah.

01:30:40.780 Gets punctured before it enters the needle?

01:30:42.940 Yeah. The fluid, yeah.

01:30:45.180 So you do it one at a time?

01:30:46.560 Yeah.

01:30:46.880 You go, ping, into a follicle, burst it open, and the egg, because a 16-gauge

01:30:52.180 needle is probably only a millimeter across.

01:30:56.740 Yeah. You suck out all the fluid, and you don't have to take it out each time. You can go from

01:31:00.960 follicle to follicle to follicle. You just have to go in typically twice, once on the right and once on

01:31:06.320 the left. Pretty interesting that that works.

01:31:08.220 Yeah. It's easiest maybe to just watch a video of it, and then you get the idea.

01:31:12.900 I'm just thinking of all the things that could go wrong, and how the needle could get gunked up

01:31:16.520 with tissue, and then you got to pull it out and put it back in.

01:31:20.180 For sure. All those things can happen.

01:31:21.140 Yeah. You know, there's always a small risk of bleeding, small risk of infection,

01:31:25.280 small risk of injury in other organs.

01:31:26.980 And this is happening, you do this on both sides, because presumably you're stimulating

01:31:30.080 both sides.

01:31:31.000 Yeah.

01:31:31.440 So how long does that procedure typically take?

01:31:33.740 Half an hour.

01:31:34.640 And you've got the embryologist next to you, and he or she is under the microscope going check,

01:31:40.080 check, check, check, check.

01:31:41.200 Yep.

01:31:41.960 He or she is validating that you indeed are getting ripened eggs, and they look different,

01:31:48.700 presumably. Like those are easy to identify under a light microscope?

01:31:51.980 Basically, they tell us they got eggs. We don't know if they're mature yet. We know

01:31:55.640 nothing about them yet.

01:31:56.700 I see.

01:31:57.080 But when we get the eggs, they go to the lab, and then the rest of the process happens there.

01:32:02.440 So in the retrieval, we're just aspirating all the follicles, trying to get as many eggs

01:32:07.040 as possible.

01:32:08.020 Okay. Then let's just assume that the woman is doing this not to just freeze her eggs, 1.00

01:32:14.840 but because she wants to get pregnant. Would you then go ahead,

01:32:19.140 and when she wakes up, have a discussion that says, we got this many eggs, how many would

01:32:23.900 you like to fertilize? How many would you like to freeze?

01:32:26.020 That discussion has happened way upstream. Typically, we're fertilizing all of them.

01:32:30.940 Yeah. There's no reason not to fertilize.

01:32:32.760 Okay. Tell me the time course now and how you move from retrieval to fertilization.

01:32:37.460 So then the eggs are sitting in the Petri dish in the lab.

01:32:41.060 What's the medium?

01:32:41.740 It is this proprietary medium.

01:32:44.600 It's proprietary?

01:32:45.520 Yes.

01:32:45.960 Meaning each lab will have its own medium?

01:32:49.280 There are commercial companies that make it, but the exact components of it, not entirely known.

01:32:54.260 So there are different companies that have different mediums?

01:32:56.660 Yes. I believe there's more than one, but it's meant to kind of emulate the fluid in the tubes,

01:33:03.280 like where fertilization would normally happen. 0.99

01:33:06.100 How much of a competitive advantage is it for an embryologist? Like how many options do they have

01:33:12.360 to choose from commercially?

01:33:14.200 Of media? I don't think there's that many media companies.

01:33:17.420 I see. Is this a huge area of innovation in the field? It must be.

01:33:21.620 Not really.

01:33:22.420 I would have guessed this would be so important.

01:33:24.520 I think they got it down.

01:33:25.560 Was there a day when this was a problem?

01:33:27.260 I'm sure.

01:33:27.840 Okay.

01:33:28.060 Yeah, maybe in the early days.

01:33:29.500 So the embryologist transfers this to the media?

01:33:31.940 Yep. A few hours later, the eggs are inseminated. So with conventional IVF,

01:33:38.220 we just put a bunch of sperm in there and let the fertilization happen by itself. With ICSI,

01:33:43.780 or intracytoplasmic sperm injection, the embryologist takes a single sperm and injects it into each egg.

01:33:50.720 And the only time again you need to do ICSI is if the sperm is so dysfunctional that it can't even

01:33:56.480 on its own with no barriers make its way to fertilization when placed in direct proximity 0.94

01:34:01.680 of an egg?

01:34:02.340 It probably could, but maybe there's too few sperm. So anytime there's a male factor,

01:34:06.900 we tend to do ICSI.

01:34:08.240 Any male factor you go straight to ICSI. 0.96

01:34:10.100 Yeah. And in fact, a lot of times it's done even when there isn't a male factor because

01:34:15.640 fertilization rate is a little bit higher with ICSI compared to IVF. In very few cases,

01:34:21.560 you don't get fertilization, so you don't want to find out, oh, by the way, sperm can't fertilize

01:34:26.460 your egg. That's the whole problem all along because then you got to throw away the eggs.

01:34:30.280 So again, for a couple listening to us now, this is something they need to be talking about with

01:34:35.860 their fertility doc, which is, hey, do you do ICSI out of the gate no matter what?

01:34:40.780 Yeah. It's a little controversial because it adds cost.

01:34:43.980 How much cost?

01:34:45.100 Probably another $1,000 or $2,000 or something. No, probably $1,000. So the data, to be clear,

01:34:51.500 shows that ICSI and IVF have similar success rates for non-male factor. But I'm just telling you that 0.74

01:34:58.880 a lot of times we're doing it anyway because we don't want to find out small, very small percentage

01:35:04.640 of cases that have zero fertilization. That's like not a good conversation.

01:35:08.560 Oh, that would be just catastrophic because you've lost those eggs too.

01:35:12.080 Right. Right. So that's part of the reason that we do it. But technically, if you just look at the

01:35:17.520 data, success rates should be the same, ICSI and conventional IVF, if non-male factor. But a lot 0.94

01:35:23.920 of times there's sperm factor, so we're doing ICSI anyway. These go into, the media sits at room

01:35:29.500 temperature. I'm sorry, at body temperature. Do you put it into a 37 degree oven?

01:35:33.320 Yeah. Body temperature in an incubator and then all the micromanipulations happening.

01:35:38.780 What are the types of manipulations that are needed to foster the right environment? How much

01:35:42.540 you're moving the fluid around? How often are you changing the media? This is like the most

01:35:46.780 important cell culture experiment of all time.

01:35:48.800 Pretty much, pretty much. To be fair, it's done by the embryologist, not by me, but they

01:35:53.120 strip the eggs first, which means they remove the cells around the eggs. Then a few hours later,

01:35:58.960 they're injecting the sperm into each egg. And then the media these days may or may not get changed

01:36:07.720 over the five or six days that we culture the embryos, trying to not have to take the embryos out

01:36:14.740 of the incubator if we don't have to kind of thing. So by the next day, usually we look at the embryos

01:36:21.020 to see, or the eggs, see if they're fertilized. Usually about 70% of the eggs fertilize. So

01:36:26.380 let's say we get 10 eggs, you can expect maybe seven of them will be fertilized. And now there's

01:36:32.060 seven embryos. So we discard the unfertilized eggs, continue to culture.

01:36:37.440 And you can tell that grossly or are you having to move them under a microscope?

01:36:40.580 Under a microscope. Yeah. And then we culture them in the Petri dish.

01:36:45.940 At this point, are they all in one dish or are you separating them?

01:36:49.540 They're in one like droplet of oil and there might be more than one droplet in each dish.

01:36:57.400 How are embryologists trained? How does one become an embryologist?

01:37:01.340 Well, there's no clear pathway. There's not a whole bunch of embryology schools.

01:37:06.220 But if I wanted to be an embryologist, what would I do?

01:37:08.240 Mostly got an apprenticeship almost. You might start working in a fertility clinic

01:37:13.220 and do some basic lab prep work initially. Most of them have some sort of undergraduate

01:37:19.000 science background, but you don't have to. But anyway, you gain experience in the lab

01:37:24.380 and then eventually you become a junior embryologist. So it's like a mentorship program.

01:37:29.180 How many years would it take, if I started tomorrow working as a lab tech who was doing

01:37:34.180 nothing but cleaning Petri dishes, how many years would it take for me to be the head

01:37:38.140 embryologist in your lab?

01:37:39.160 It might take four to five years. Take a while. Now there's some formal schools available as well

01:37:45.640 that with online programs, with some in-person components.

01:37:49.660 Not to take anything away from what you do, but you could have the best fertility doctor if they 1.00

01:37:55.580 don't have a good embryologist. You're not going to have great success rates.

01:37:59.060 Oh yeah. Yeah. I would say the lab is almost more important than what we do because there's

01:38:04.560 just more variability. But luckily, at least the United States labs are pretty good. But yeah,

01:38:10.200 that's one of the most important things. I mean, because I used to work in a lab,

01:38:14.240 I just can think of a hundred ways that could get screwed up, contaminated, jostled,

01:38:20.140 all these things that can go wrong. Yeah. Super important. Yeah. So most of the success rate,

01:38:24.700 probably more related to what happens in the lab than anything I do or one of my physician

01:38:29.780 colleague does. I guess the question is, well, let's finish the story and then I want to come back to

01:38:34.560 So how many days, you go to 14 days of this? No, five days, six days. And depending if we're

01:38:41.940 doing a fresh transfer or freezing the embryo, so a fresh transfer, we sometimes-

01:38:46.340 So you'll do both, right? We do both.

01:38:47.920 Yeah. Although these days, most of the time we're freezing.

01:38:51.140 Because you're doing genetic screening?

01:38:52.380 Because we're doing genetic testing, right?

01:38:54.000 Okay. So let's go through that example then.

01:38:56.040 Okay. So we're culturing these embryos in the Petri dish for five to six days. Then we look at them

01:39:01.020 again. The ones that have made it to that stage, which is usually only half of them. So remember,

01:39:06.040 you're seven. Now maybe there's three or four.

01:39:08.400 So what explains that?

01:39:10.920 So most likely the ones that didn't make it are the chromosomally abnormal ones. Remember,

01:39:15.900 we talked earlier about those ones not making it.

01:39:18.340 And the reason it's only half is because by definition, you're doing this in women who tend

01:39:22.420 to be a bit older. Not that one would do this, but just as a thought experiment, if you did this

01:39:27.760 exact thing in 18-year-old girls, presumably you'd have a much higher success rate. 1.00

01:39:33.780 Yeah. We call that the blastulation rate is a little bit higher in younger women. Also, 0.97

01:39:39.080 you have more eggs and more embryos, of course. But yes, the blastulation rate, the ones that make

01:39:45.300 it to day five or six is a lower percentage the older a woman is because a higher proportion of 0.99

01:39:51.040 those embryos are just going to be abnormal. So the ones that make it to day five or six are more

01:39:55.380 likely to be normal, but not necessarily normal. So we can also do genetic testing on those embryos,

01:40:02.020 which involves biopsying them. So we take a few cells from the embryo, freeze the embryos.

01:40:08.020 So yeah, let's talk about that. So how many cells do you have at five days again?

01:40:11.360 Altogether, you might have like 60 to 80 cells.

01:40:14.160 Okay. So you take two or three of those.

01:40:16.520 Five or six.

01:40:17.240 Five or six.

01:40:17.960 Yeah. And they're from-

01:40:19.300 The perimeter.

01:40:19.900 The trophoblast. Not the embryo directly, but the cells surrounding the embryo.

01:40:23.800 But you still have full genetic material there.

01:40:26.900 And so you do that for each and every egg, every embryo, sorry. And then you freeze each embryo?

01:40:32.220 Yep.

01:40:32.840 Tell me what the freezing process is like.

01:40:34.620 So the freezing process these days is one called vitrification, it's called. And it's like

01:40:39.820 this special kind of freezing that doesn't result in ice crystals.

01:40:44.300 So how do you do that?

01:40:45.300 There's a process. It happens in the lab. There's a machine that does it,

01:40:49.440 that lowers the temperature.

01:40:50.560 So the rate at which they lower the temperature-

01:40:53.660 Right. It's rapid.

01:40:54.680 Okay. So it's like a liquid nitrogen dump, basically.

01:40:57.320 Right. As opposed to old days when we did slow freezing. So it becomes like a glass-like

01:41:02.200 state without crystals. It works really well. And the survival is really high.

01:41:06.880 And then you store them at what temp? Like liquid nitrogen temp?

01:41:09.700 Yeah.

01:41:10.020 Yep. It's not like in your freezer.

01:41:11.520 No. At home.

01:41:12.880 And then how long does it take typically to get the genetic results?

01:41:15.080 Typically within a week or two.

01:41:16.240 Okay. What depth of genetic testing is being done here? Are you doing whole genome sequence? Or are

01:41:23.240 you just looking at a handful of SNPs that are pre-identified as the ones that matter?

01:41:30.440 So it's evolved over time. And I should say it's still very controversial because

01:41:34.800 there's always a risk of harming the embryos. You're only looking at a few cells. So is it really

01:41:40.480 representative of the embryo? I mean, we do it a lot. And the data definitely shows that if you transfer

01:41:45.680 normal embryo, it has a very high chance of implanting. But the issue is recently has been,

01:41:51.640 are we discarding embryos that are maybe normal because we think they're abnormal based on the

01:41:56.320 genetic testing, but the genetic testing is flawed?

01:41:59.520 Presumably, genetic testing is really easy to identify aneuploidy. The chromosomal analysis is

01:42:05.800 trivial.

01:42:06.180 Yes. It's geared up to do that. Right. So most of the time we're using something called next

01:42:09.720 generation sequencing, which is very high level sequencing, but it's not whole genome sequencing.

01:42:14.840 So you're getting- Targeted.

01:42:16.200 Yeah. And you're looking mostly at chromosomal abnormalities, unless you know that the couple

01:42:21.660 is a carrier for some genetic mutation that you also want to screen for.

01:42:26.800 Yeah. So let's say one of the parents, well, this would be a bad example, but-

01:42:32.880 Cystic fibrosis, like let's say both patients are carriers.

01:42:35.060 So both of them are a carrier for CF. And so there's a one in four chance that you're going

01:42:40.900 to get two copies of CF.

01:42:42.180 Right.

01:42:42.460 So then you're looking directly for the CF genes.

01:42:44.360 Exactly. Exactly.

01:42:45.380 Beta-thal, sickle cell, the standard-

01:42:47.720 Yeah. There's a whole bunch of them.

01:42:48.360 Okay.

01:42:48.500 Right. And part of the screening, we didn't mention it, but most people doing IVF will

01:42:52.780 get carrier screening to see if they're carriers for any genetic mutations.

01:42:57.020 But that's a pretty common scenario where you have two people that are CF carriers, neither

01:43:01.000 of whom have CF. Most of those people would say, I'm going to do IVF because I don't want

01:43:05.440 to take the chance. And then what about people who come in and say, oh, but one of us is each

01:43:10.000 an APOE4 carrier. So we're each a 3-4 and we would really like to not select a 4-4 as

01:43:17.060 an example. So one, are you able to look at that? And two, does that start to cross an

01:43:22.400 ethical line?

01:43:23.040 Yeah. It's a little more controversial when you're talking about-

01:43:26.220 Non-deterministic adult consequence genes.

01:43:28.400 With variable penetrants, right? You may or may not get Alzheimer's or whatever it is. So

01:43:33.500 it's a little more controversial, but we're kind of going in that direction, I would say. We're

01:43:39.160 definitely going probably in the near future towards whole genome sequencing where we can

01:43:44.380 pick up even mutations that happen de novo, what we call de novo, right? You might not be a carrier,

01:43:49.760 but it might just happen randomly. So you could pick up some disease that way. And then what you're

01:43:55.060 talking about is-

01:43:56.360 Like BRCA. 1.00

01:43:57.180 Well, BRCA, yeah. Often we know ahead of time, the patient's carrier, we can test for it.

01:44:01.560 LPA for cardiovascular disease.

01:44:03.940 Yeah. There's a whole bunch of things. So people are starting to talk about

01:44:07.640 polygenic screening embryos, but it's a little more controversial because the science isn't quite

01:44:13.140 settled yet. And it's one thing if you're already doing IVF and we have these embryos here and we're

01:44:19.620 just going to add another layer of testing, like which one of these embryos is at higher risk for

01:44:24.580 like diabetes or hypertension, whole different story. If you're saying, oh, you should do IVF-

01:44:29.820 Because of-

01:44:30.440 Because we want to get the embryo with the lowest risk of these diseases. So we're not quite there.

01:44:35.100 There's a very controversial, plus it's expensive. And we already talked about cost barriers and

01:44:40.400 there are ethical issues as well. Are we now, is it a form of positive eugenics and that type of

01:44:46.720 thing? So that particular type of testing is still controversial, but anti-employed testing,

01:44:52.380 testing for chromosomal abnormalities is pretty routine, pretty standard.

01:44:56.900 Now, there was a day when people weren't doing any genetic testing and the embryo selection was

01:45:02.640 just based on morphology, right?

01:45:04.580 Yes. Yeah. Which is back in the days where we had to transfer more than one embryo because we didn't

01:45:09.680 know. You could look at two embryos and they could look both normal, but one of them is

01:45:14.440 chromosomally abnormal and one's not, and you can't really tell. So we had to transfer more embryos

01:45:19.200 to get decent pregnancy rates. Now with genetic testing, because we know that a chromosomally 0.97

01:45:25.560 normal embryo has a pretty high chance of implanting, not a hundred percent, like maybe 70, 75%. So

01:45:31.780 there's still reasons. For some reason, that's not the whole story because even chromosomally normal

01:45:36.880 embryos sometimes don't implant.

01:45:38.460 Yeah. That's lower than I would have guessed.

01:45:40.680 Is it?

01:45:41.000 70 to 75% for something that's chromosomally normal. I would have guessed at that stage,

01:45:45.940 given all the selection that's taking place. What is the concordance between, let's go one step

01:45:51.480 further, chromosomally genetically normal and good morphology?

01:45:57.340 There's good correlation. Yeah. We use both.

01:46:00.840 If there's discordance there, which one are you relying on or are you discarding unless you have

01:46:05.120 concordance that's positive for both?

01:46:07.500 In reality, the ones that have poor morphology aren't even frozen or biopsied, they're discarded

01:46:12.660 because we know-

01:46:13.760 So we select it out.

01:46:14.640 Yeah, you're selected out. So there might be a little bit of difference in morphology between

01:46:17.920 the ones that you've actually decided to freeze and biopsy and keep, and you presumably have the

01:46:23.800 genetic testing on all of them. You would preferentially, of course, transfer the ones that are

01:46:28.460 chromosomally normal, even if the morphology grade is a little bit lower.

01:46:32.700 So you have selected out bad morphology. Let's just say you harvested 15, you fertilized 10,

01:46:41.580 seven had good morphology, six came back genetically good. Those would be reasonable numbers?

01:46:48.920 Yeah. The six out of seven is high.

01:46:50.840 Yeah. Okay. So five came back genetically good.

01:46:53.420 Let's say, in a young person.

01:46:54.880 Yeah. So you got one third of what you harvested, you could implant. You're saying each of those is

01:47:01.560 70 to 75% success rate. And yet you would only implant one at a time.

01:47:05.800 Yeah.

01:47:06.540 Which is interesting because if you implanted two, let's do the math, you're talking about-

01:47:12.720 50% chance roughly-

01:47:13.820 That's right. I was just going to say-

01:47:14.820 Twins. Yeah. Which is high.

01:47:16.800 Too high. We just can't take that risk.

01:47:18.960 I mean, obviously we believe in patient autonomy. Patient usually gets to make that decision, but-

01:47:24.660 You're going to make the case for where that's not a great idea.

01:47:26.640 You want a healthy baby in the end, you want a healthy mom.

01:47:29.060 Yeah. Okay. So now let's talk about, now it's time to implant. So how does that process work?

01:47:33.740 So that process is much less complicated, but equally important. So usually it's timed. It has

01:47:40.520 to happen at a certain time in the cycle. So we either use the woman's natural cycle 1.00

01:47:44.520 to time it and time it at the time that implantation would normally occur, which is the second half of

01:47:51.060 the cycle. Or we use what we call a controlled program cycle, where we basically give the woman 1.00

01:47:56.400 the hormones and then time the transfer to happen at a specific time. The actual process, kind of like

01:48:01.960 a pap smear. It basically doesn't require any anesthesia or anything. We do do it under ultrasound

01:48:07.480 guidance, so abdominal ultrasound. We thaw one of the embryos, draw it up in a little catheter with a

01:48:13.500 little syringe on the end, place the speculum in the vagina, and then just pass the catheter 1.00

01:48:18.800 through the cervix. And we're looking on the ultrasound for the placement.

01:48:22.660 And where are you implanting it?

01:48:24.280 One and a half centimeters to two centimeters from the top of the uterus. So a few centimeters 0.90

01:48:30.300 through the cervix.

01:48:32.080 How do you make sure it doesn't come out?

01:48:34.760 I mean, you can't, but it doesn't usually. You put it in there, I describe it more like peanut

01:48:39.140 butter in there. It's not like you can stand up and it comes out.

01:48:41.480 What's the total volume you're injecting?

01:48:44.120 50 microliters, really small.

01:48:46.980 What is the inside of a uterus look like at that stage? You've timed it so that this is

01:48:52.880 a uterus that doesn't have a lining yet.

01:48:54.800 Does have a lining.

01:48:55.800 How thick is the lining?

01:48:57.000 It's about seven to 10 millimeters.

01:49:01.200 But it's going to get a heck of a lot thicker. This is technically only about 14 days past her

01:49:05.180 period. Or are you doing it artificially more into the luteal phase?

01:49:08.600 So it's roughly seven days or so after ovulation, right?

01:49:13.860 I got it. Yes, yes, yes.

01:49:14.780 So the lining is thickened already.

01:49:16.640 Okay.

01:49:17.020 And that's one of the things we check with ultrasound before we do the transfer to make 0.91

01:49:21.500 sure the lining is...

01:49:22.500 What does that actually look like? Is it tentacle fingers or...

01:49:26.940 On the ultrasound, which is how we assess it, basically the two walls of the uterus are

01:49:32.260 opposing each other. It's not like you can see...

01:49:35.300 It's a potential space, not a real space.

01:49:36.940 Potential space, exactly. On the ultrasound, the lining has a different echo density than...

01:49:42.460 The wall itself, yeah.

01:49:43.360 Right. So we can measure the thickness. And basically, the combined thickness of the two

01:49:49.200 opposing walls has to be at least seven millimeters or so.

01:49:53.160 And if you get in there and do the ultrasound and it's not, are you going to come back and try to

01:49:57.720 do it another day? And have you lost that egg because it's been thawed? Or can you keep that egg in the

01:50:03.360 medium now?

01:50:04.460 We essentially assess the lining a week before we do the transfer. So we would not thaw the embryo

01:50:10.840 unless we were sure of the lining.

01:50:11.920 Until it's go time.

01:50:12.560 Yeah. Because once it's thawed, I mean, you can refreeze it, but...

01:50:15.860 No, no. I'm sure it doesn't do as well.

01:50:17.260 Not a good idea.

01:50:17.940 Yeah.

01:50:18.260 Okay. So I see. So once you put that egg in there...

01:50:20.860 Embryo.

01:50:21.420 Sorry, that embryo in there closer to the top of the uterus, it's largely being held in place by the

01:50:26.500 opposition of the wall. And then are you done or are you still doing ongoing hormone therapy?

01:50:30.860 Sometimes we give supplemental progesterone. That's another hormone that helps maintain

01:50:35.260 the pregnancy. And then usually 12 to 14 days later, the patient has her first pregnancy test.

01:50:41.720 Hopefully she's pregnant. We usually follow the pregnancy for the first few weeks. 1.00

01:50:45.760 And then she transfers to her non-IVF.

01:50:47.960 Or midway. Yeah.

01:50:49.040 Wow. It's just kind of amazing that this all works.

01:50:51.940 Yeah. I've been doing it for 30 plus years and I still find it fascinating. Yeah.

01:50:56.580 Okay. So how often does a woman go through all of this and for whatever reason you can't get enough 1.00

01:51:05.240 eggs or the eggs you get are not chromosomally normal and her next alternative is an egg donor?

01:51:13.560 Unfortunately, more often than we would like. Again, it depends on the age of the patient,

01:51:18.440 but sometimes patients do multiple cycles. Maybe they don't have any normal embryos or

01:51:23.460 maybe even the normal embryos we transfer don't take or a number of different things can happen.

01:51:28.980 So the most common reason someone would need an egg donor is usually maternal age. So someone who's

01:51:35.200 older and has tried to get pregnant with their own eggs hasn't worked for whatever reason. And then

01:51:40.880 now she's looking at egg donation as an option. That works really well. So usually egg donors are young 0.78

01:51:47.240 women in their twenties, early thirties. Sometimes they produce multiple eggs and then the age of 0.95

01:51:54.080 the uterus doesn't seem to matter as much. So the success rate with donor egg is quite high. It's about

01:52:01.220 70, 75%. Whereas for women over 40 using their own eggs, success rate might be 10 to 20% per cycle.

01:52:10.560 Per cycle. Yeah. Wow. 10 to 20% for a 40 year old woman. Yeah. Untested embryos or they may not get 0.99

01:52:18.240 any embryos, normal embryos. Yeah. I did not realize it was that low. Yeah. How many times can a young

01:52:25.180 woman be an egg donor before you worry about, is there anything you worry about if you're counseling 0.65

01:52:30.400 these women? I assume the same women are coming to you as egg donors. Yeah. Sometimes people do it 1.00

01:52:35.000 multiple times. Sometimes they just do it once. Does it pose any risk? They're essentially undergoing the

01:52:40.160 IVF process themselves or at least the first half of it. There's the risks we talk about ovarian

01:52:45.120 hyperstimulation, which is rare, risks associated with the retrieval, anesthesia. But is there anything

01:52:51.220 that restricts her ability to get pregnant later in life? No. Barring any complications from major 0.99

01:52:57.080 complications, it does not seem to impact future fertility. What is the typical fee that's collected

01:53:03.200 by an egg donor? It's usually between $5,000 and $10,000 depending on where you live. Okay. That's a

01:53:09.940 lot of money. It's a lot of money for a two-week period. Yeah. And so a woman could do that a couple 1.00

01:53:16.300 times a year if she wanted to? So the guidelines up to six times. Six times a year? No. Six times

01:53:21.500 lifetime. Oh. Okay. So up to six times. And that's a little bit arbitrary, but the professional society

01:53:28.600 has decided that's kind of a good number of times. Most people don't do it that many times. They might

01:53:33.900 just do it once or twice. And so what is, and maybe you don't do this, I don't know, but women 1.00

01:53:39.780 who undergo egg donation or IVF via egg donation, what do you discuss with them about the appropriateness

01:53:47.060 of timing in explaining to the children that they have a different genetic mother? Before anybody does

01:53:54.560 egg donation or even before they donate eggs, we always have them meet with one of our mental health

01:53:59.260 therapists just as a psychoeducational visit to go over these types of questions and best practices

01:54:06.000 around what to tell the child, when to tell the child. General rule is tell them early and tell them

01:54:13.020 often. You basically want to normalize the thing and you definitely want to be the ones to tell them

01:54:19.920 and you don't want them to find out by some other means, like somebody contacts them on 23andMe or

01:54:26.580 something like that. And early means what? Telling them before they understand reproduction? Like

01:54:32.460 what are you telling them? Yeah, I mean, again, it's a little outside my area of expertise, but when

01:54:37.600 they're quite young, like it could be like four to six years of age, it might depend on the child and

01:54:43.420 how mature they are, et cetera. But basically there's different ways to introduce the concept.

01:54:49.320 Obviously if it's a same-sex couple or if it's a single person, it might happen earlier as opposed to

01:54:55.200 a straight couple. So if someone's listening to this and they're trying to figure out how to select

01:55:01.900 a good IVF clinic, what are the things they should be looking for? Because I would have to assume that

01:55:10.280 it's like any other field of medicine. Not all doctors and not all clinics are created equal. And

01:55:16.940 just because you see a lot of advertising doesn't tell you anything. So in other words, you're going to

01:55:22.480 have to become a very, very intelligent consumer. For most people, this will be the single most

01:55:28.320 expensive out-of-pocket healthcare expense they have. Yeah, that's true.

01:55:33.640 And so it's not just that it's the most expensive healthcare decision they're ever going to make.

01:55:38.300 It might be one of the most consequential as well. And yet I know what I suggest to people. When

01:55:44.700 someone says, Peter, you know, my wife and I are thinking about getting IVF. What do you think?

01:55:48.300 I just go down the rabbit hole of like, here's a hundred questions I would ask.

01:55:52.860 And it usually begins with, tell me your success rate individually. I don't care about the national

01:55:59.180 success rate. It means nothing to me. So how would you counsel someone who's trying to come up with

01:56:04.380 their checklist of questions to ask? These days is a little bit easier because obviously there's

01:56:08.840 the internet and there's suggested questions online you could look at. It's true there is some

01:56:13.360 variability amongst clinics, although there's a lot of consolidation happening in the field as well.

01:56:18.000 So a lot of the practices are becoming common to most clinics, but some of it is practical,

01:56:24.140 right? Like which clinics are close to where you live? Because as- 0.52

01:56:27.040 You have to go in and get these ultrasounds. 0.89

01:56:28.440 Yeah, you got to go in every few days. So you can't be going to another state. Most people can't.

01:56:32.920 But in most major cities, you have multiple options.

01:56:35.580 In most major cities, that's true. So you're right about individual clinic success rates,

01:56:41.740 although technically it's hard to use those to compare them to each other because you don't

01:56:47.800 necessarily know the population, right? You don't have the patient population, right?

01:56:49.760 So how do you normalize it?

01:56:51.080 Right. So one thing for sure, look at the success rates. And we're one of the few fields of medicine

01:56:56.460 where actually you can get clinic-specific success rates.

01:57:00.140 You mean publicly it's available?

01:57:01.400 Yeah, it's available.

01:57:02.660 Where do you find it?

01:57:03.340 Well, the CDC, until recently, there is a law actually that says you have to report every

01:57:09.240 IVF cycle and the success rate that was passed in the 90s. So because of that, the CDC tracks this.

01:57:14.860 Although all the people that work in that department were fired recently. So you don't

01:57:18.780 know what's going to happen with that. But also our professional organization is called

01:57:22.640 Society of Assisted Reproductive Technology, has a website. It's called sart.org is the URL.

01:57:29.000 And all the clinics in the U.S. or most of them are on there. And they have to report their success

01:57:35.320 rates. And they're published every year. There's usually like a two-year lag because the babies have

01:57:40.000 to be born and everything. So I would send people to that website first. Look at the clinics in your

01:57:45.420 area. Look at the success rates. Keeping in mind that populations might be different in different

01:57:51.380 clinics. I probably would go to a clinic that does a sufficient volume. You have to do at least 100

01:57:57.800 cycles, I would say. But ideally, more than that.

01:58:01.920 Your clinic has how many doctors?

01:58:04.020 Our clinic has about six doctors.

01:58:06.320 How many total cycles do you guys do a year?

01:58:08.340 We do six to 800 retrievals a year. There's a lot of variability. There's some clinics that do

01:58:14.780 thousands. There are some that do like 50. So that would be one factor that I think is important,

01:58:20.260 just volume.

01:58:21.600 And you have how many embryologists?

01:58:23.640 We have something like nine embryologists.

01:58:26.380 Wow.

01:58:26.620 Yeah. There is a shortage of embryologists nationwide and reproductive endocrinologists because the

01:58:32.800 demand for IVF is going up. So I would definitely look at the clinic success rates, look at the

01:58:37.500 volume. The other thing with the internet, especially you can look at patient reviews,

01:58:43.060 word of Mao. Got to take those with a grain of salt, right?

01:58:45.940 Yeah. They tend to be negative selecting.

01:58:47.400 Right. Not everybody who has a great experience is necessarily going to post it on Reddit.

01:58:51.480 But everyone who has a bad one does.

01:58:52.940 Yeah. Yeah. So you have to take that with a grain of salt. But there are objective ways. And you can

01:58:57.040 also like interview your doctor.

01:58:58.860 Yeah. What are questions you should be asking of the doctor that are independent of the objective

01:59:03.540 metrics that we might have just discussed?

01:59:05.460 You can ask about their philosophy, about protocols, about things like add-ons, like genetic testing,

01:59:13.080 for example. It's like, are you a clinic where everybody is encouraged to do a genetic testing?

01:59:18.760 That's not necessarily the clinic I would choose. You talk to the patient about the pros and cons,

01:59:23.440 and you let the patient decide. And we do a lot of genetic testing, so it's not like I'm against it

01:59:28.620 or anything. But you want to get a sense of the vibe of the clinic. Are they just interested in money?

01:59:35.880 Not that doctors ever think like that, but you know what I mean? So sometimes it takes having a

01:59:40.760 consultation with one or more clinics to see where you feel more comfortable. I'm a little bit biased

01:59:46.000 towards some academic centers just because our missions include education and research, et cetera.

01:59:52.820 But there's several very excellent private clinics as well.

01:59:58.260 What would be some red flags if you're going through this process? How much of a delta is there

02:00:03.420 in cost within a same city? Or did prices tend to converge within a given geography?

02:00:08.360 Yeah. Within a given geography, they're pretty similar and it's not cheap.

02:00:12.460 Yeah. So what are we at today? Fully loaded cost.

02:00:14.760 So, you know, an IVF cycle is probably around $20,000 per cycle.

02:00:18.520 But that doesn't include genetic testing or does?

02:00:20.620 Including genetic testing.

02:00:22.240 Per cycle.

02:00:23.460 But how does that compare to 20 years ago? Is that more or less inflation?

02:00:26.540 Prices like most things have gone up.

02:00:28.960 It has?

02:00:29.420 Yeah.

02:00:29.700 Okay. I guess it should go up just based on the cost of labor that goes into all these things.

02:00:34.340 Yeah. And there's innovations.

02:00:34.960 Even though the genetic testing is coming down.

02:00:36.600 Yeah. Innovations and things like that. You're right. Like you think as volume goes up,

02:00:40.640 eventually prices go down, but that hasn't quite happened. As new things get added,

02:00:44.580 then it just tends to become more expensive.

02:00:47.280 And most people are probably still paying out of pocket. Most people are not getting this covered by insurance.

02:00:51.520 Again, depends where you live.

02:00:52.660 Yeah. Yeah. But across the country.

02:00:53.800 Yeah. I think there are now 24 states that offer some kind of fertility coverage. About 15 of them

02:01:00.380 include IVF. So you're right. Most places, they're paying out of pocket if your employer

02:01:05.840 doesn't happen to offer infertility insurance coverage. Yeah.

02:01:09.560 Yeah. So red flags, communication with the clinic. So a lot of your experience is going to be

02:01:17.100 communicating with nurses and coordinators.

02:01:20.700 Yeah. Just setting up appointments.

02:01:22.120 Yeah. You want to get a sense of what that is like, because that could be stressful if it's not

02:01:27.120 smooth. And oftentimes our clinic included, sometimes it's not smooth. I mean, there've been

02:01:31.980 some things we try and do like texting and apps and things to make the communication easier and

02:01:38.660 it doesn't always work the way it's supposed to. You want to get time with your doctor. So

02:01:42.860 some clinics, you hardly ever see the doctor and you see maybe the ultrasonographer. Not that that's

02:01:48.480 bad, but it's kind of nice. Some patients prefer to have that more frequent interaction with their

02:01:53.560 actual provider.

02:01:54.220 So there's probably a sweet spot in volume where it's probably an inverted U shape where if they're

02:01:58.440 too low, they don't have the reps. If they're too high, it's a bit of a sweatshop and a factory

02:02:02.820 and you want in the middle there. Let's pivot now and talk about a few other things. So what's on the

02:02:08.180 horizon medically for extending fertility? So there's a study going on at Columbia that's looking at the

02:02:14.540 use of rapamycin to extend fertility in women. Now, I have to be honest with you, there was a day when I

02:02:20.900 knew what the study was and what the inclusion criteria were. I don't at the moment. I'm assuming

02:02:25.820 you are more familiar with this than I am. What is the question that is being asked and how is it

02:02:31.600 being asked in this study?

02:02:33.560 So there's a lot of interest in extending fertility. Up until 100 years ago, women were basically dying

02:02:40.120 at 50 in the average age of menopause. So it's a recent phenomenon that we're actually living a third

02:02:44.960 of our lives post-menopause. Infertility starts to decline way before you go through menopause. So

02:02:50.040 there's a lot of interest in trying to extend fertility. Now, of course, egg freezing,

02:02:54.700 which we haven't talked about yet, is one of the ways you can extend fertility and it works 0.99

02:02:58.700 pretty well as long as you're young when you freeze your eggs. But again, it's a relatively recent

02:03:04.580 phenomenon. You're not usually covered by insurance and it's expensive, et cetera. So it's not the answer.

02:03:09.740 Because you're paying basically half the IVF cycle to harvest and then you're paying to freeze.

02:03:15.400 Yeah, exactly.

02:03:16.320 What's the cost of freezing?

02:03:17.260 Well, $10,000 for the cycle and then about $1,000 a year for storage.

02:03:22.180 And you're recommending that if a woman came to you at 20 and said, I just want to double down 0.98

02:03:28.060 on my career right now. I want to do X, Y, and Z. I think I want to have kids. I at least want the

02:03:33.500 optionality. When should I freeze by? Are you going to just say, do it now? Because no.

02:03:38.340 I wouldn't recommend all women in their 20s freeze their eggs because most of those eggs will never 1.00

02:03:43.200 be used. So you'd be doing it for nothing because most of those women will probably not need IVF and 1.00

02:03:47.760 get pregnant spontaneously, right? 0.97

02:03:49.140 Got it. Okay.

02:03:49.860 The sweet spot we think is like early to mid 30s. That's where it makes the most sense.

02:03:55.060 Because you're about to get to the probability cliff where it starts to really decline.

02:03:59.880 Right. If you think you might want to have kids, but you're not in a place in your life where you

02:04:04.120 think that's going to happen in the next few years, then doing it early to mid 30s is probably the

02:04:09.460 time where it's most cost effective. Very high likelihood that you will use them, if not for

02:04:13.860 the first kid, maybe for the second kid. And it might be worth spending $10,000 and $1,000 a year.

02:04:21.120 And a thousand bucks a year.

02:04:21.480 And do you freeze them? You freeze every egg you retrieve?

02:04:26.920 Only the mature ones.

02:04:28.440 Okay.

02:04:28.960 Yeah.

02:04:29.460 And what's the, for a typical 30 year old, you're going to get what we talked about earlier?

02:04:35.760 Probably 10 to 15 per cycle, sometimes more, but that's average.

02:04:38.400 And how many do you recommend a 30 year old do?

02:04:41.260 Yeah. So there's some calculators online. So the younger you are, the fewer eggs you need because

02:04:46.500 more of them are going to be normal. So someone in 30, I think 10 to 20 would give you

02:04:51.260 a decent chance of success. No guarantees. There's never any guarantees, but studies show that even

02:04:56.860 if people use those eggs and then are not successful, the fact that they did something

02:05:01.300 proactively, there's some psychological benefit in doing that. So even if ultimately doesn't work

02:05:06.680 out or you don't end up using them, but at that age, maybe 10 to 20, as you get closer to 40,

02:05:12.220 you might need 20 to 40 or 50, which is not practical for most people because you can't do that many

02:05:18.400 cycles and it's expensive and there's risks involved. So I think egg freezing is a great

02:05:23.840 option for women. I also think as a society, we should try to make it easier, obviously, for women

02:05:28.820 to have kids during their peak reproductive years and their twenties and thirties, a whole different

02:05:34.440 question. But I think having options is a good thing.

02:05:37.320 So back to the rapamycin question, they're basically saying, look, is there a way that we

02:05:41.740 could push that out a little bit? And so how is the study testing this?

02:05:46.860 So rapamycin, as some of your listeners may know, is used in other anti-aging type contexts.

02:05:53.100 There's some animal data that shows that maybe rapamycin might extend fertility in that, remember

02:06:00.540 the egg cell death that we talked about earlier, by like preventing that to some degree so that the

02:06:07.180 eggs last longer and you're fertile for more years. So there's some data in mice primarily.

02:06:14.700 There's some data show that it's not helpful as well. So the data I would say is mixed in animal

02:06:19.500 models. And the study at Columbia is actually trying to test it in humans. I believe it's a

02:06:24.320 few months study where they're giving relatively low dose of rapamycin. I forget exactly, maybe five

02:06:30.200 milligrams daily.

02:06:31.500 Daily, not weekly.

02:06:32.800 I think it's daily.

02:06:33.960 Okay. Interesting.

02:06:34.660 We'll pull it up and put it in the show notes. I should have known this.

02:06:38.120 And then I think their outcome markers, AMH, I believe it was just that hormone. So I don't know.

02:06:43.720 It's a relatively inexpensive study. They're not invasively looking at follicles.

02:06:48.060 What you'd have to believe then is in just a period of a few months, you could pick up a signal

02:06:53.900 of more or less AMH reduction.

02:06:57.560 Right. And even if you can, like, what does that mean really?

02:07:00.460 This study could be negative. If the study is positive, it's interesting. If it's negative,

02:07:05.960 it probably doesn't tell us much. If it's only three to six months.

02:07:09.500 Right. To really do the study, I mean, you'd need long-term.

02:07:12.820 Right. You need pregnancy outcomes or at least menstrual menopause, age of menopause. So that 0.59

02:07:20.260 would take for a long time and you'd have to take it for many years, probably.

02:07:24.560 That's going to be a really difficult question to answer in humans.

02:07:28.880 Yeah. Again, because of the animal data not being consistent. Some studies show,

02:07:33.740 yeah, maybe it's helpful, but other studies show that it might be actually harmful because of the

02:07:37.880 way it acts as being immunosuppressive and things. So certainly for any listeners trying to conceive,

02:07:43.900 I would not recommend rapamycin. But yes, I'm curious about the data coming out of Columbia and

02:07:48.980 other studies.

02:07:49.580 Are there any other things that a woman can do to maximize her fertility beyond we've already 0.99

02:07:55.660 addressed sort of PCOS, we've already addressed the metabolic stuff, but we hear things all the

02:08:01.700 time like stress, sleep. I mean, these things seem self-evident, but what would be the most common

02:08:08.380 things you would be saying to a woman who is otherwise experiencing iatrogenic, for lack of a better

02:08:15.060 word, infertility?

02:08:17.180 Yeah, I think all those things are important, like lifestyle factors. They're rarely the sole cause of

02:08:23.080 infertility, but they can certainly exacerbate infertility as well as any other disease. So I think the

02:08:29.400 lifestyle factors that promote health are generally the same lifestyle factors that promote fertility. So

02:08:37.480 healthy diet.

02:08:38.900 Is there anything we can say more on that? Like, what is a healthy diet as it pertains to fertility? Is it

02:08:44.260 different? Does a woman who's getting ready to conceive, does she need more fat in her diet, 1.00

02:08:49.240 for example?

02:08:49.780 Yeah, yeah. As you probably know, the data on diet is not great for anything, especially not fertility.

02:08:56.520 So I would say there's very little evidence that there's a particular diet that's good for fertility

02:09:02.700 that's different than what's good in general. So for most of my patients, I recommend the Mediterranean

02:09:08.960 diet. That diet is palatable to most people and has a fair amount of evidence that it's reasonably

02:09:16.340 healthy. And that's a lot of fruit and vegetables, whole grains, protein, mostly from fish and olive

02:09:22.480 oil and those types of things. It's not that different from what I would recommend for anybody.

02:09:28.620 By the way, I think I said iatrogenic. I meant idiopathic, but you know what I meant.

02:09:31.840 Yes.

02:09:32.000 So what about supplements? I'm sure you get asked this question all the time. There's no shortage of

02:09:36.880 over-the-counter supplements that people report increased fertility. I get asked these questions

02:09:42.480 all the time and have blank stares because I don't know. Is there anything you can point to? And I love

02:09:47.480 frameworks. So maybe one framework is, are there supplements that correct legitimate deficiencies

02:09:53.360 like vitamin D or B vitamins where we could make a case that supplementing with these things

02:09:58.180 happen? I'm talking beyond just the prenatal vitamins that are obvious and necessary. We'll

02:10:02.500 leave that to the side because it's so self-evident versus supplements that are kind of more grab bag

02:10:07.500 mystery supplements where you're not actually correcting some obvious deficiency, but we think

02:10:11.860 it might increase fertility. 0.51

02:10:13.940 So the data around supplements, even less robust than the data around diet, I would say. Yes. If you're

02:10:20.300 correcting deficiencies, I think you can make a case for that. So it was a lot of women, 1.00

02:10:25.000 reproductive age women are iron deficient, for example, and they might need to be on iron 1.00

02:10:29.600 supplements. You mentioned prenatal vitamins. Obviously, folic acid is important for anybody

02:10:34.120 trying to get pregnant. People who live in Portland, Oregon, like I do, we tend to be vitamin D deficient.

02:10:40.280 So I usually recommend vitamin D for people. But other supplements specifically for fertility,

02:10:46.480 the ones I most commonly hear about are things like CoQ10 or DHEA is another one. And there's

02:10:53.740 some data that it might be helpful. Again, it's not very robust.

02:10:58.540 DHEA?

02:10:59.520 DHEA.

02:11:00.300 Which just increases endogenous testosterone production.

02:11:03.980 Improves egg quality. Like who knows how it works.

02:11:06.700 Yeah. I mean, the data isn't great.

02:11:08.620 Might improve libido. 1.00

02:11:09.880 Maybe. I think people have studied that. It doesn't work so well.

02:11:13.100 It is a weak androgen. You're right. Yeah. The data is not very promising. But so for most of these

02:11:18.120 things, the data is not there and probably will never be there, right? Because there's

02:11:22.480 symptoms that aren't there to do those studies. So it probably doesn't hurt though. And so I'm

02:11:27.720 relatively supportive. The patient wants to take CoQ10. There's some data around it. Sure.

02:11:31.720 Do you think it's just psychological where if they take it and they feel that they're doing

02:11:36.320 something better, it reduces their stress around it? Because for me, I can't help but think that

02:11:41.100 stress has such a negative impact on fertility.

02:11:44.380 Oh, for sure.

02:11:45.020 And on many aspects of health.

02:11:46.300 For sure.

02:11:46.640 But it's so difficult to quantify. We don't have a biomarker for stress. Even measuring

02:11:51.340 cortisol doesn't actually tell you anything about the experience of stress. And so I just think

02:11:56.780 so many negative health outcomes are a result of it. And therefore, anything that a person can do

02:12:01.280 to improve their stress.

02:12:02.620 I agree with you. And if taking supplements helps with that, sure, I'm all for it.

02:12:06.300 Yeah. I'm not advocating that we should be going crazy on it with no evidence. But I wonder if

02:12:10.500 any of the efficacy of those things is mediated through that reduction of stress.

02:12:14.100 Possibly. Yeah. And as long as it's not harmful, that's great. And when we say the

02:12:18.660 data isn't there, it's just because it doesn't mean that it doesn't work. It's just nobody's

02:12:22.540 shown one way or another whether it works. So it's quite possible. CoQ10 has some effect

02:12:27.440 that we don't know about. And my feeling is if I don't think it's harmful and patient wants

02:12:32.400 to take it, maybe helps with their stress. Sure. I'm for that. Other things, stress, almost

02:12:38.320 everybody has some degree of stress in their lives, some more than others, unfortunately.

02:12:42.920 But it's really hard to get rid of all the stress. Like, it's not helpful to tell a patient,

02:12:47.140 well... You just need to be less stressed.

02:12:48.060 You just need to be less stressed. So I'm like, okay, now what? But finding ways to cope with

02:12:53.580 the stress is really what we're talking about. And that can be different for different people.

02:12:56.960 For some people, it could be exercise. For some people, it could be meditation. For some people,

02:13:01.360 whatever, mindfulness, whatever, whatever it is. But definitely it's important. Same as sleep. And

02:13:08.000 we talked about diet. Exercise is important.

02:13:12.480 Do you caution women or do we know anything about too much exercise for women who are trying 0.95

02:13:18.160 to conceive? I mean, we certainly hear stories about college athletes and women who are doing a lot

02:13:22.800 are actually having difficulty even maintaining a regular menstrual cycle. So if you're dealing with

02:13:26.480 a woman when you're taking that social history and you're trying to understand, what are some clues to 0.99

02:13:31.120 you that her exercise might actually be too much and that might be impacting her fertility? 0.86

02:13:35.720 Extreme exercise can be associated with fertility issues. Although I think for most patients,

02:13:41.580 the benefits of exercise, as we know.

02:13:43.580 Yeah. What is extreme in this case?

02:13:45.180 If it causes any change in a person's cycle. So for some of the more extreme athletes,

02:13:50.260 sometimes their periods will stop altogether. There's a condition called REDS. It's relative 1.00

02:13:55.100 energy deficiency in sport. And basically the body is very smart. If it thinks there's not enough

02:14:00.860 energy around to support a pregnancy because we're expending it all on this exercise, we're just

02:14:05.800 going to shut the whole thing down and it works really well. But the patient stops menstruating. 0.96

02:14:10.040 So obviously they're going to have difficulty getting pregnant if they're not ovulating. If you're 0.72

02:14:14.660 not menstruating, it means you're not ovulating. Also has other implications for things like bone

02:14:19.060 health. Because the ovary, in addition to making eggs, also makes estrogen. And estrogen is super 0.60

02:14:23.680 important for bone health. So one lesson for the listeners, keep track of your, we talked about

02:14:29.840 semen analysis being kind of a marker of other health outcomes. Your periods are also a marker.

02:14:35.900 Of course, if you're on hormonal contraception, you might not know what your natural cycle is doing.

02:14:40.840 But if your cycles are irregular or if you're not having them at all, or if they're super painful or

02:14:45.380 they're super heavy, and sometimes you don't know what's super painful or super heavy because

02:14:49.220 nobody talks about anything. But thankfully this generation of young women is talking more

02:14:54.420 and there's the internet and et cetera. But don't wait till you're ready to try to get pregnant to 1.00

02:14:58.540 figure that out. There may be something important you need to know way ahead of time. So.

02:15:03.600 And we've already talked about obesity, but on the other side of that, is there a certain body fat

02:15:08.560 level beneath which fertility is also impacted?

02:15:11.800 Yeah, there's not a cutoff, but certainly being overweight or obese can impact fertility and being

02:15:17.140 severely underweight. For the underweight people, there's a similar mechanism. If your brain thinks

02:15:22.500 there's just not enough.

02:15:23.980 It's usually going to manifest through amenorrhea.

02:15:26.540 Yeah, exactly. Exactly. So healthy weight, healthy diet, exercise, sleep, disrupted sleep

02:15:33.200 could affect ovulation and fertility. Stress, we mentioned all these things, all the things you

02:15:39.160 mentioned in your book as well, are all the same things that are important for fertility.

02:15:44.440 Lastly, what do you think is the most promising area of research? And if we're sitting here in 10

02:15:50.020 years and we're talking about this and we're looking back at the last decade, what do you

02:15:55.980 imagine you will be most excited about from an innovation perspective?

02:16:00.180 It's a very exciting field of medicine. There's always sort of innovations happening. I think,

02:16:05.600 let's see, genetic testing will continue to evolve as we learn more about genetics. I think that'll

02:16:10.620 play a bigger role. Automation in the lab. A lot of the steps we talked about earlier are like

02:16:16.420 literally embryologists sitting at the microscope doing these things, but now there's some companies

02:16:22.760 developing these lab on a chip concepts where like you put in the egg, put in the sperm,

02:16:28.500 an embryo comes out.

02:16:29.340 So microfluidics or?

02:16:30.780 Yeah. Microfluidics, the whole process being automated. It's very interesting, right? And it

02:16:37.760 could potentially improve access if you could put these labs.

02:16:41.480 So do you see this as more of a cost reduction or more of a success improvement?

02:16:46.200 Maybe both because reduce error potentially. Usually the cost of things tends to go up anytime

02:16:52.620 there's an innovation before it comes down. Maybe ultimately it'll come down, but imagine costs

02:16:57.480 will increase. So that's kind of an exciting area. In vitro maturation, that's where the eggs are

02:17:04.560 maturing in the Petri dish instead of in a woman's body. So potentially in the future, a woman wouldn't 1.00

02:17:10.360 have to take all these injections and just take the immature eggs, put them in the Petri dish, and then

02:17:16.380 give the Petri dish the medications, if you will. That's in very sort of early stages, not quite as

02:17:23.060 successful as conventional IVF yet. So we're not quite there.

02:17:26.280 I assume because it's difficult to harvest unmature follicles?

02:17:30.260 Partly, and even that maturation process, we haven't quite gotten it down like it happens

02:17:34.900 in the body. Other things, a real game changer would be something like in vitro gametogenesis,

02:17:42.380 which is making eggs and sperm potentially from skin cells. So even if you run out of eggs,

02:17:49.100 if we could take like a skin biopsy and reprogram that cell to make an egg, then potentially,

02:17:56.140 anybody. Where are we in that?

02:17:58.180 Very early. I think we'll see it eventually. It's been done in mice. So we're probably 10 to 20 years

02:18:04.760 away. What's the obstacle?

02:18:07.120 Basically, reprogramming skin cells. It just, the whole process is very complicated and not easy.

02:18:14.980 People are trying, there are a couple of companies that are trying to do it.

02:18:16.940 Is the challenge taking the skin cell back to a stem cell and then the stem cell into-

02:18:21.980 Differentiating it.

02:18:22.760 Yeah. And which of those two steps do we think is harder? Skin cell back to stem cell or stem cell

02:18:27.880 into egg?

02:18:29.140 I think they're both hard. I don't know. There's a couple of different approaches, including

02:18:32.840 we work, do research in this area as well, where we're taking essentially the nucleus from a skin

02:18:39.120 cell and putting it-

02:18:40.520 Into an egg.

02:18:41.320 Into an egg.

02:18:41.500 And just replacing the genetic material.

02:18:43.220 Yes, exactly. So we don't have to reprogram the skin cell.

02:18:46.780 And is it easy to separate the chromosomes?

02:18:49.420 No.

02:18:50.140 Okay. I was going to say-

02:18:51.420 No. It's very complicated because it's meiosis. It's hard for it to happen efficiently and

02:18:56.480 equally, et cetera. So we're working on it, but we're probably 10, 20 years away. But that

02:19:01.780 would be an alternative way to get to that. But then you need donor eggs. So that has its

02:19:06.820 own limitations because it's not like donor eggs are easy to come by either.

02:19:10.760 Yeah. That's true. Although I guess what it does is it helps the older woman who is able to make 0.99

02:19:18.340 follicles, but they're just aneuploidic.

02:19:20.760 Exactly.

02:19:21.200 You have a solution to that problem.

02:19:22.480 Yeah. Yeah. Another thing we're working on is something called mitochondrial replacement therapy,

02:19:27.180 where basically similar concept. You were taking, like you have an older woman, let's say,

02:19:33.240 she undergoes IVF. You have a donor that undergoes IVF, but you take the nucleus out of the older egg

02:19:41.500 and you put it in a younger egg. So essentially the cytoplasm is from the young egg, including the

02:19:46.820 mitochondria. So we think part of the aging is just like other aspects of aging, you know,

02:19:52.000 acquired mutations in the mitochondria. So you have young cytoplasm, young mitochondria,

02:19:56.340 maybe those eggs will do better or that nucleus will do better in that young egg. Unfortunately,

02:20:02.160 we can't do that in the United States legally, but we're doing trials in other countries.

02:20:07.820 This is kind of a remarkable field. Again, it's still amazing to me how well this works.

02:20:13.040 If you think about it, this is, and I don't mean this in a disparaging way at all,

02:20:17.320 it's very brute force. It's very mechanical. And yet we're, as a field, I think having an enormous

02:20:23.860 impact that is relatively recent when you sort of think about the timescale of this.

02:20:27.640 So it seems to me that early intervention is better. Your point about women who have any sort 1.00

02:20:35.980 of irregularity in their cycle, if they're in their teens or twenties, if for no other reason

02:20:42.820 beyond just the discomfort of it at the moment, getting this looked at now is a great way to get

02:20:49.240 ahead of an infertility problem 10 years hence. For sure.

02:20:53.240 That to me is a very important takeaway that I don't think is probably appreciated enough. And

02:20:57.880 while I don't think we have a high listenership of 18 year old girls, my guess is that message

02:21:03.440 through parents who are listening might make its way to potential future patients that would find

02:21:09.000 themselves on your doorstep. It's also comforting to hear just how high the probability of success is

02:21:15.840 in the modern era today. And it sounds to me like we're converging on quality. Whereas I would

02:21:22.660 imagine this was a field that was a bit like the wild west 20 years ago, where you had a bunch of

02:21:27.100 charlatans out there who were maybe not charlatans is the wrong word, but just low quality practitioners.

02:21:31.800 And I'm guessing today with consolidation of groups, we're seeing less and less of that.

02:21:35.460 More standardization. Yes, for sure.

02:21:37.420 I'm still blown away at the concept of the embryologist and what's required to do that and

02:21:43.740 how that we don't have a more formal training path, especially given that you said that we have a

02:21:47.600 shortage of such people. That seems like an incredibly rewarding career for somebody.

02:21:52.420 So hopefully we can foster that. Paula, this has been great. I feel between this podcast and the

02:21:57.540 podcast on male fertility, I have a much better sense of this and how to address it. Both very

02:22:02.500 different problems, but completely complementary. Related, for sure.

02:22:05.120 Yeah. Appreciate your time and your expertise.

02:22:07.080 Thanks for inviting me. It's been fun. Thanks for having me.

02:22:09.160 Thank you for listening to this week's episode of The Drive. Head over to peteratiamd.com forward slash

02:22:17.100 show notes. If you want to dig deeper into this episode, you can also find me on YouTube,

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The Peter Attia Drive - June 09, 2025

#352 ‒ Female fertility： optimizing reproductive health, diagnosing and treating infertility and PCOS, and understanding the IVF process ｜ Paula Amato, M.D.

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